Renal pathology

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Renal pathology

  1. 1. <ul><li>RENAL PATHOLOGY </li></ul><ul><li>Diseases affect </li></ul><ul><li>a) glomeruli (often immunological) </li></ul><ul><li>b) tubules (toxic, infectious) </li></ul><ul><li>c) interstitium (toxic, infectious) </li></ul><ul><li>d) vascular </li></ul><ul><li>Disease in one area usually results in </li></ul><ul><li>damage or disease on neighboring areas </li></ul><ul><li>Large functional reserve </li></ul><ul><li>a) > 75% destruction before impairment </li></ul>www.freelivedoctor.com
  2. 2. <ul><li>Congenital Anomalies </li></ul><ul><li>Review page 961 , “Robbins and Cotran” PATHOLOGIC BASIS OF DISEASE . 7 TH ed. </li></ul><ul><li>Understand and describe the following </li></ul><ul><li>congenital anomalies of the kidney </li></ul><ul><li>a) agenesis </li></ul><ul><li>b) hypoplasia </li></ul><ul><li>c) ectopic kidney </li></ul><ul><li>d) horseshoe kidney </li></ul>www.freelivedoctor.com
  3. 3. <ul><li>GLOMERULI </li></ul><ul><li>Network of capillaries </li></ul><ul><li>a) lined by fenestrated endothelium </li></ul><ul><li>b) basement membrane </li></ul><ul><li>c) podocytes (“foot processes”) </li></ul><ul><li>Glomeruli capillary wall </li></ul><ul><li>a) lined with fenestrated endothelium ( 70- 100 nm) </li></ul><ul><li>b) glomerular basement membrane (GBM) </li></ul><ul><li>i) consist of collagen (type IV), heparan sulfate, laminin, glycoproteins </li></ul>www.freelivedoctor.com
  4. 4. - Type IV collagen forms network to which glycoprotein's attach c) visceral epithelial cells (podocytes; “foot processes”) i) composed of interdigitating processes embedded to basement membrane ii) adjacent foot processes are separated by 20-30 nm filtration slits bridged by thin diaphragm (nephrin) d) entire glomerulus is supported by mesangial cells i) lying between capillaries www.freelivedoctor.com
  5. 5. <ul><li>ii) phagocytic, contractile, proliferate, secretion of biologically active mediators </li></ul><ul><li>- modified smooth muscle cells </li></ul><ul><li>iii) involved in many types of GN </li></ul><ul><li>Glomeruli </li></ul><ul><li>a) very permeable to H 2 O and small solutes </li></ul><ul><li>b) impermeable to proteins (~ 70 kDa or larger; i.e., albumin) </li></ul><ul><li>c) “glomerular barrier function” </li></ul><ul><li>i) selective permeability based on: </li></ul><ul><li>- size </li></ul><ul><li>- charge: cationic more permeable </li></ul>www.freelivedoctor.com
  6. 6. ii) podocytes important in maintaining this “function” - slit diaphragm maintain size- selectivity by specific proteins 1.- NEPHRIN : extend towards each other from neighboring podocytes comprising the slit diaphragm !! 2.- PODOCIN : intracellular (podocyte) protein where nephrin attaches - mutations in genes encoding these proteins give rise to nephrotic syndrome (i.e., glomerular disease) www.freelivedoctor.com
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  11. 11. <ul><li>Clinical Manifestations </li></ul><ul><li>Termimology </li></ul><ul><li>a) Azotemia :  BUN and  creatinine </li></ul><ul><li>i) related to  GFR </li></ul><ul><li>- prerenal azotemia:  RBF, hypoperfusion w/out parenchymal damage </li></ul><ul><li>- postrenal azotemia: obstruction of urine flow below level of kidney </li></ul>www.freelivedoctor.com
  12. 12. <ul><li>b) when azotemia becomes associated with a variety of clinical S & S and biochemical abnormalities  UREMIA </li></ul><ul><li>Major Renal Syndromes </li></ul><ul><li>a) Nephritic syndrome : glomerular disease, hematuria, mild  moderate proteinuria, azotemia, edema,  BP </li></ul><ul><li>i) classic presentation of post streptococcal GN </li></ul><ul><li>b) Nephrotic syndrome : heavy proteinuria (> 3.5 g/day), hypoalbuminemia, severe edema, hyperlipidemia and lipiduria </li></ul>www.freelivedoctor.com
  13. 13. c) Acute renal failure : oliguria/anuria, recent onset of azotemia, can result from GN, tubular or interstitial disease d) Nephroliathiasis : renal stones, renal colic, hematuria, recurrent stone formation e) Chronic renal failure : 4 stages i)  renal reserve: GFR ~ 50% normal BUN & creatinine normal, pt. asymptomatic, more susceptible to develop azotemia ii) renal insufficiency: GFR 20-50% of normal, azotemia, anemia,  BP, polyuria/nocturia (via  concentrating ability) www.freelivedoctor.com
  14. 14. iii) renal failure : GFR less than 20-25% kidneys cannot regulate volume, ions: edema, hypocalcemia, metabolic acidosis, uremia with neurological, CV and GI complications iv) end stage renal disease : GFR < 5% of normal, terminal stage of uremia www.freelivedoctor.com
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  16. 16. <ul><li>Glomerular Disease </li></ul><ul><li>Chronic GN one of most common causes </li></ul><ul><li>of chronic renal failure </li></ul><ul><li>Glomerular disease often associated with </li></ul><ul><li>systemic disorders such as: </li></ul><ul><li>a) diabetes mellitus </li></ul><ul><li>b) SLE </li></ul><ul><li>c) amyloidosis </li></ul><ul><li>d) vasculitis </li></ul><ul><li>- pts. with manifestations of glomerular disease should be considered for these systemic syndromes, etc. </li></ul>www.freelivedoctor.com
  17. 17. <ul><li>GN characterized by one or more of the </li></ul><ul><li>following (inflammatory diseases of </li></ul><ul><li>glomerulus) </li></ul><ul><li>a) hypercellularity : </li></ul><ul><li>i) cell proliferation of mesangial cells or endothelial cells </li></ul><ul><li>ii) leukocyte infiltration (neutrophils, monocytes and sometimes lymphocytes) </li></ul><ul><li>iii) formation of crescents </li></ul><ul><li>- epithelial cell proliferation (from immune/inflammatory injury) </li></ul><ul><li>- fibrin thought to elicit this injury (TNF, IL-1, IFN-  are others) </li></ul>www.freelivedoctor.com
  18. 18. b) basement membrane thickening i) deposition of immune complexes on either the endothelial or epithelial side of GBM or w/in GBM itself ii) thickening of GBM proper as with diabetes mellitus (diabetic glomerulosclerosis) c) hyalinization (hyalinosis) and sclerosis i) accumulation of material that is eosinophilic and homogeneous - obliterates capillary lumen of glomerulus (sclerotic feature) www.freelivedoctor.com
  19. 19. <ul><li>- result of capillary or endothelial injury. Usually end result of various forms of glomerular damage (intraglomerular thromboses, accumulation of other metabolic materials) </li></ul><ul><li>Since etiology of primary GN is unknown, </li></ul><ul><li>classification is based on histology. </li></ul><ul><li>Subdivided: </li></ul><ul><li>a) diffuse (all glomeruli) </li></ul><ul><li>b) global (entire glomerulus) </li></ul><ul><li>c) focal (portion of glomeruli) </li></ul><ul><li>d) segmental (part of each glomerulus) </li></ul><ul><li>e) mesangial (affecting mesangial region) </li></ul>www.freelivedoctor.com
  20. 20. <ul><li>Pathogenesis of Glomerular Disease/Injury </li></ul><ul><li>Little is known regarding etiology or </li></ul><ul><li>triggering </li></ul><ul><li>Immune mechanisms underlie most </li></ul><ul><li>cases of primary GN and many of the </li></ul><ul><li>secondary cases </li></ul><ul><li>a) 2 forms of Ab-associated injury </li></ul><ul><li>i) injury resulting from soluble Ag-Ab deposits in glomerulus </li></ul><ul><li>ii) injury from Ab reacting in-situ with glomerulus </li></ul><ul><li>- insoluble fixed glomerular Ag </li></ul><ul><li>- molecules planted w/in glomerulus </li></ul>www.freelivedoctor.com
  21. 21. <ul><li>Examples </li></ul><ul><li>In Situ Immune Complex Deposition </li></ul><ul><li>a) Ab act directly with intrinsic tissue Ag </li></ul><ul><li> “ planted” in the glomerulus from the circulation </li></ul><ul><li>b) 2 forms of Ab-mediated glomerular injury </li></ul><ul><li>i) anti-GBM Ab-induced nephritis </li></ul><ul><li>- Ab directed against fixed Ag in GBM </li></ul><ul><li>- in humans spontaneous AGBM nephritis is autoimmune disease </li></ul>www.freelivedoctor.com
  22. 22. - Ab bind along GBM forming a “linear pattern” - sometimes AGBM Ab cross react with BM of lung  GOODPASTURE SYNDROME - < 1% of GN cases - some cases show severe glomerular damage and rapidly progressive crescentic GN ii) Heymann nephritis - a form of membranous GN - Ab bind along GBM in “granular pattern” www.freelivedoctor.com
  23. 23. <ul><li>c) Trigger for induction of autoimmune Ab is </li></ul><ul><li> unclear </li></ul><ul><li>i) ETX </li></ul><ul><li>ii) mercuric chloride </li></ul><ul><li>iii) graft-vs.-host reaction </li></ul><ul><li>Ab can react with “planted” Ag in GBM </li></ul><ul><li>a) cationic Ag binding to anionic GBM sites </li></ul><ul><li>b) bacterial byproducts </li></ul><ul><li>c) IgG deposition in mesangium </li></ul>www.freelivedoctor.com
  24. 24. www.freelivedoctor.com
  25. 25. <ul><li>re: Ab-mediated injury  Ag-Ab deposition in GBM is major pathway of glomerular injury !! </li></ul><ul><li>a) largest proportion of cases of GN are granular immune pattern along the GBM or mesangium </li></ul><ul><li>Cell mediated immune GN </li></ul><ul><li>a) sensitized T cells can cause glomerular injury, in absence of immune deposits </li></ul><ul><li>i) may occur in some forms of rapidly progressive GN </li></ul>www.freelivedoctor.com
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  27. 27. <ul><li>Mediators of immune injury </li></ul><ul><li>seen as loss of glomerular barrier function </li></ul><ul><li>a) proteinuria </li></ul><ul><li>b)  GFR in some instances </li></ul><ul><li>Complement-leukocyte mechanism </li></ul><ul><li>a) well established </li></ul><ul><li>i) activated complement (C5a)  </li></ul><ul><li> neutrophils and monocytes </li></ul><ul><li>- release proteases  degrade GBM </li></ul><ul><li>ii) ROS </li></ul><ul><li>iii) some are neutrophil-independent </li></ul><ul><li>- C5-C9 (lytic component; membrane attack complex) </li></ul>www.freelivedoctor.com
  28. 28. <ul><li>- Membrane attack complex stimulate growth factors (TGF)  GBM thickening </li></ul><ul><li>iv) direct cytotoxicity </li></ul><ul><li>Other mechanisms of glomerular injury </li></ul><ul><li>a) epithelial cell injury </li></ul><ul><li>i) can be induced by Ab to visceral epithelial cell Ag </li></ul><ul><li>ii) toxins </li></ul><ul><li>iii) cytokines </li></ul><ul><li>iv) loss of foot processes </li></ul><ul><li>- caused by alterations in nephrin </li></ul>www.freelivedoctor.com
  29. 29. b) renal ablation GN i) any renal disease   GFR (30-50% of normal) - lead to end stage renal failure ii) patients develop proteinuria and diffuse glomerulosclerosis - initiated by unaffected glomeruli  hypertrophy to maintain function  single nephron hypertension  damage www.freelivedoctor.com
  30. 30. <ul><li>Glomerular Syndromes and Disorders </li></ul><ul><li>Nephrotic Syndrome </li></ul><ul><li>a) massive proteinuria (> 3.5 g/day) </li></ul><ul><li>b) hypoalbuminemia </li></ul><ul><li>c) generalized edema </li></ul><ul><li>d) hyperlipidemia and lipiduria </li></ul><ul><li>Initial event is derangement of GBM  </li></ul><ul><li>increasing permeability and progressive </li></ul><ul><li>loss of plasma proteins  </li></ul><ul><li>hypoalbuminemia  decrease in plasma </li></ul><ul><li>colloid osmotic pressure  edema   </li></ul><ul><li>plasma volume   aldosterone </li></ul>www.freelivedoctor.com
  31. 31. <ul><li> ANP, GFR   water and solute retention by </li></ul><ul><li>kidney  exacerbation of edema (anasarca; </li></ul><ul><li>massive amounts of edematous fluid); </li></ul><ul><li>hypoalbuminemia   lipoprotein production </li></ul><ul><li>by the liver </li></ul><ul><li>In children < 15 yrs, nephrotic syndrome </li></ul><ul><li>almost always caused by primary renal </li></ul><ul><li>disease (~ 98 %) </li></ul><ul><li>In adults nephrotic syndrome may often </li></ul><ul><li>be associated with secondary renal </li></ul><ul><li>disease </li></ul>www.freelivedoctor.com
  32. 32. www.freelivedoctor.com
  33. 33. <ul><li>GLOMERULAR DISEASES </li></ul><ul><li>( NONINFLAMMATORY ) </li></ul><ul><li>Membranous Glomerulopathy (epithelial </li></ul><ul><li>cell and BM disease) </li></ul><ul><li>a) most common cause of nephrotic syndrome in adults (C5-C9 cytotoxic) </li></ul><ul><li>b) diffuse thickening of glomerular capillary wall !! </li></ul><ul><li>c) most cases are idiopathic </li></ul><ul><li>i) most believed to be autoimmune </li></ul><ul><li>d) most cells are normocellular or only mildly hypercellular </li></ul>www.freelivedoctor.com
  34. 34. e) believed to be caused by i) deposition of immune complexes w/in capillary wall - IgG and C3 ii) formation of in situ immune complexes iii) refer to Heymans nephritis and Goodpasture syndrome iv) classified as non inflammatory since there is NO cellular proliferation f) In adults, a frequent association is with carcinoma !! (i.e., melanoma, lung and colon) www.freelivedoctor.com
  35. 35. <ul><li>g) associated with systemic infections </li></ul><ul><li>i) HBV </li></ul><ul><li>ii) SLE </li></ul><ul><li>h) associated with certain drug treatments </li></ul><ul><li>i) gold, penicillamine, NSAID </li></ul><ul><li>Clinical </li></ul><ul><li>a) variable </li></ul><ul><li>i) spontaneous remission or renal failure w/in 10-15 yrs </li></ul><ul><li>b) persistent proteinuria w/ normal function </li></ul><ul><li>c) better response to corticosteroids in children vs. adults </li></ul>www.freelivedoctor.com
  36. 36. d) Progression of disease i) stage I : small granular subepithelial deposits ii) stage II : “spikes” of BM protrude between deposits of electron dense material (e.g., IgG, C3) iii) stage III : deposits of electron dense material are incorporated into GBM iv) stage iv : GBM very distorted and damaged www.freelivedoctor.com
  37. 37. www.freelivedoctor.com
  38. 38. <ul><li>Minimal change disease (Lipoid </li></ul><ul><li>nephrosis; (Epithelial cell disease)) </li></ul><ul><li>a) major cause of nephrotic syndrome in </li></ul><ul><li>b)  children < 15 yrs; peak 2-6 yrs i) also in adults with nephrotic syndrome (~ 20 %) </li></ul><ul><li>c) effacement of “foot” processes </li></ul><ul><li>d) glomeruli show only “minimal” changes </li></ul><ul><li>e) most patients are boys who usually present prior to 6 yrs of age </li></ul><ul><li>i) selective proteinuria (albumin) </li></ul><ul><li>ii) history of recent Ag exposure ?? </li></ul><ul><li>f) idiopathic (sometimes follows respiratory infection or routine immunizations) </li></ul>www.freelivedoctor.com
  39. 39. Minimal Change Disease www.freelivedoctor.com
  40. 40. www.freelivedoctor.com
  41. 41. g) T cell involvement suggested i) HL patients present w/ similar S & S ii) epithelial cell diseases have altered T ell function h) loss of lipoproteins through the glomeruli  accumulates lipids in proximal tubule cells  foamy cytoplasm. Together with lipids in the urine  LIPOID NEPHROSIS i) remission w/in 8 weeks with use of corticosteroid use (very dramatic response is one hallmark of this disease) j) relapses do not tend to progress to chronic renal failure www.freelivedoctor.com
  42. 42. <ul><li>k) development of azotemia should suggest incorrect diagnosis of minimal change disease </li></ul><ul><li>l) in absence of complications, outcome of patients with epithelial cell disease is same as general population </li></ul><ul><li>Focal segmental glomerulosclerosis </li></ul><ul><li>(epithelial cell and BM disease) </li></ul><ul><li>a) some glomeruli exhibit segmental areas of sclerosis whereas others are normal </li></ul><ul><li>b) nephrotic syndrome </li></ul><ul><li> </li></ul>www.freelivedoctor.com
  43. 43. c) occurs in the following setting: i) associated with other conditions - HIV - heroin addiction - sickle cell disease - morbid obesity ii) secondary event - IgA nephropathy iii) adaptive process to loss of kidney - renal ablation - advanced stages of other renal diseases (e.g., hypertension) iv) primary disease (e.g., idiopathic focal segmental glomerulosclerosis) www.freelivedoctor.com
  44. 44. d) most common cause of nephrotic syndrome in USA i) Hispanics and African Americans e) differs from minimal change disease i) higher incidence of hematuria, reduced GFR, and hypertension ii) poor response to corticosteroids iii) proteinuria is non selective iv) progression to chronic glomerulosclerosis v) IgM and C3 trapping on sclerotic segments www.freelivedoctor.com
  45. 45. vi) whether this is a specific disease or is an evolution of minimal change disease is unresolved !! - degeneration of visceral epithelial cells hallmark of FSGN - similar cell damage as seen in minimal change disease vii) genetic basis - NPHS1 gene  encodes nephrin - several mutations of this gene give rise to congenital nephrotic syndrome of the Finnish type (CNF) www.freelivedoctor.com
  46. 46. Focal segmental glomerulosclerosis www.freelivedoctor.com
  47. 47. <ul><li>- NPHS2 gene </li></ul><ul><li>- encodes to podocin </li></ul><ul><li>- mutations give rise to steroid resistant nephrotic syndrome in children </li></ul><ul><li>Paraproteinemic nephropathies </li></ul><ul><li>a) abnormally elevated immunoglobulin or </li></ul><ul><li> immunoglobulin fragments (i.e., paraproteins) may cause renal disease </li></ul><ul><li>i) present in blood and/or urine </li></ul><ul><li>ii) renal diseases include </li></ul><ul><li>- multiple myeloma </li></ul><ul><li>- Waldenstrom macroglobulinemia </li></ul><ul><li>- cryoglobulinemia </li></ul>www.freelivedoctor.com
  48. 48. <ul><li>Multiple myeloma </li></ul><ul><li>a) neoplasm of Ig producing plasma cells </li></ul><ul><li>b) occurs in 5 th decade </li></ul><ul><li>c) more than 50% of all patients with multiple myeloma have renal involvement </li></ul><ul><li>i) hypercalcemia </li></ul><ul><li>ii) hyperuricemia </li></ul><ul><li>iii) renal infections </li></ul><ul><li>iv) renal lesions are of three types </li></ul><ul><li>- tubular and interstitial lesions </li></ul><ul><li>- amyloidosis </li></ul><ul><li>- light chain deposition disease </li></ul>www.freelivedoctor.com
  49. 49. 2. Waldenstrom macroglobulinemia a)  serum IgM b)  blood viscosity c) renal involvement results in partial or total occlusion of glomerular capillaries 3. Cryoglobulinemia a) IgM or IgG b) defined by their capacity to precipitate at 4  C c) renal disease is often immune complex mediated d) microthrombi in glomeruli e) mesangial & endothelial cell proliferation www.freelivedoctor.com
  50. 50. <ul><li>Hereditary nephritis (Alport syndrome) </li></ul><ul><li>a) most often present as recurrent hematuria </li></ul><ul><li>b) structural defects in GBM </li></ul><ul><li>i) specific molecular defect affecting type IV collagen </li></ul><ul><li>c) usually does not present with nephrotic syndrome and proteinuria </li></ul><ul><li>d) more severe in men </li></ul><ul><li>i) die by age 40 </li></ul><ul><li>e) progressive hearing loss (high frequencies) </li></ul><ul><li>f) ocular defects most often  the lens </li></ul>www.freelivedoctor.com
  51. 51. <ul><li>Benign familial hematuria (thin GBM </li></ul><ul><li>disease) </li></ul><ul><li>a) presents as recurrent hematuria in childhood or young adults (similar to Alport syndrome) </li></ul><ul><li>b) no progression to renal failure (unlike Alport syndrome) </li></ul><ul><li>c) reduced thickness of GBM (capillary site) </li></ul><ul><li>d) one of most important causes of asymptomatic hematuria </li></ul><ul><li>e) IgA nephropathy and this disease are two most major diagnostic considerations of asymptomatic hematuria </li></ul>www.freelivedoctor.com
  52. 52. <ul><li>GLOMERULAR LESIONS ASSOCIATED WITH SYSTEMIS DISEASES </li></ul><ul><li>Diabetic glomerulosclerosis (Kimmelstiel- </li></ul><ul><li>Wilson Disease) </li></ul><ul><li>a) diabetic microangiopathy </li></ul><ul><li>i) small arteries, arterioles and capillaries) </li></ul><ul><li>- hyaline arteriosclerosis in diabetics involves both afferent and efferent arterioles </li></ul>www.freelivedoctor.com
  53. 53. ii) occur by progressive accumulation of GBM material - severity and duration of hyperglycemia !! ?? b) etiology of proteinuria not known i) non-nephrotic proteinuria ii) nephrotic c) earliest lesion is thickening of GBM d) followed by glomerular enlargement e) “diffuse glomerulosclerosis” refers to enlarged glomeruli w/expanded mesangium and diffusely thickened GBM www.freelivedoctor.com
  54. 54. f) nodular glomerulosclerosis (i.e., Kimmelstiel-Wilson Disease) – highly specific for diabetes g) one of leading causes of chronic renal failure in USA h) 2 processes play role in diabetic glomerular lesions i) metabolic defect (i.e., glycosylation end products that: -  GBM thickening -  mesangial matrix ii) hemodynamic effects: - glomerular hypertrophy (  GFR) - develop of glomerulosclerosis www.freelivedoctor.com
  55. 55. Diabetic glomerulosclerosis www.freelivedoctor.com
  56. 56. <ul><li>i) Clinical </li></ul><ul><li>i) proteinuria usually mild </li></ul><ul><li>ii) nephrotic syndrome present  renal failure w/in 6 yrs. </li></ul><ul><li>- severe proteinuria usually associated with other signs of advanced diabetes (i.e., retinopathy) </li></ul><ul><li>Amyloidosis </li></ul><ul><li>a) deposits of amyloid w/in glomeruli </li></ul><ul><li>i) mostly light chain AA or AL type </li></ul><ul><li>ii) Congo red amyloid positive deposits mainly in mesangium and capillaries </li></ul>www.freelivedoctor.com
  57. 57. Amyloid nephropathy www.freelivedoctor.com
  58. 58. <ul><li>b) clinical </li></ul><ul><li>i) nephrotic syndrome </li></ul><ul><li>ii) progressive glomerular destruction leads to death from uremia </li></ul><ul><li>Henoch-Schönlein Purpura </li></ul><ul><li>a) purpuric skin lesions on legs, arms and buttock </li></ul><ul><li>b) abdominal pain, vomiting, intestinal bleeding, arthralgias and renal abnormalities (hematuria, proteinuria, nephrotic syndrome) </li></ul><ul><li>c) not all these S & S need to be present </li></ul>www.freelivedoctor.com
  59. 59. d) disease most common in children i) 3-8 yrs e) does occur in adults where disease is more severe i) may develop rapidly progressive form of glomerulornephritis with many crescents f) onset often follows upper respiratory infection i) IgA deposits in mesangium which has led to concept that IgA nephropathy (purely a renal disease) and Henoch-Schönlein Purpura are spectra of same disease www.freelivedoctor.com
  60. 60. <ul><li>Glomerular Diseases (INFLAMMATORY) </li></ul><ul><li>(“GLOMERULONEPHRITIS”) </li></ul><ul><li>Inflammatory lesions of glomerulus </li></ul><ul><li>characterized by hypercellularity which </li></ul><ul><li>may be diffuse or focal + proliferation </li></ul><ul><li>a) Diffuse types of glomerulornephritis </li></ul><ul><li>i) post infectious </li></ul><ul><li>ii) membranoproliferative </li></ul><ul><li>iii) some lupus forms </li></ul><ul><li>b) Focal types of glomerulornephritis </li></ul><ul><li>i) IgA </li></ul><ul><li>ii) other lupus forms </li></ul>www.freelivedoctor.com
  61. 61. c) glomerular injury may be either global (entire glomerulus) or segmental d) glomerulornephritis clinically characterized by the NEPHRITIC SYNDROME i) may present with only portions of these S & S (i.e., hematuria) ii) on occasion, proteinuria may predominate e) different forms of GN are differentiated via microscopy www.freelivedoctor.com
  62. 62. f) neutrophils contribute to  cellularity, particularly in children i) many neutrophils in glomeruli referred to as “exudative” g) proliferation of podocytes and Bowman’s capsule (visceral and parietal epithelium, respectively) i) leads to formation of “crescents” - highly cellular lesions - extend from Bowman’s capsule into glomerulus having shape of crescents. These are severe lesions (associated with necrosis, early and fibrosis, late) www.freelivedoctor.com
  63. 63. <ul><li>Pathogenesis of inflammatory GN </li></ul><ul><li>Immunologic injury </li></ul><ul><li>a) trapping of circulating immune complexes </li></ul><ul><li>b) in situ immune complex formation </li></ul><ul><li>c) activation of alternative complement </li></ul><ul><li>d) cell mediated processes </li></ul><ul><li>Circulating immune complex nephritis </li></ul><ul><li>a) glomerular trapping of circulating Ag-Ab v complexes. </li></ul><ul><li>i) glomerulus as “innocent bystander” </li></ul><ul><li>- penetrate GBM than are  </li></ul><ul><li>- trapped in GBM </li></ul>www.freelivedoctor.com
  64. 64. b) confirmed by EM i) presence of subepithelial “humps” ii) peripheral granular staining directed - IgG - C3 c) alternatively, circulating immune complex do not penetrate GBM but localize to i) mesangium or subendothelium d) trapping is affected by: i) size and charge of aggregates ii) glomerular hemodynamics iii) presence of vasoactive substances www.freelivedoctor.com
  65. 65. e) Ag may be exogenous or endogenous i) exogenous - bacterial Ag induced by 1. Strep infections 2. bacterial endocarditis 3. viruses (HBV) ii) endogenous - DNA in pathogenesis of lupus 2. In Situ immune complex formation a) Goodpasture Syndrome b) Ag (endogenous) already embedded in GBM i) Ab binds !! ii) linear localization of IgG along GBM www.freelivedoctor.com
  66. 66. c) Ag-Ab interaction activates complement ! i) rapidly progressive GN occurs 3. Alternative complement activation a) focal glomerulornephritis i) caused by IgA b) form of membranoproliferative GN 4. Cell-mediated Immunity a) no direct evidence for any specific GN caused by cell mediated processes i) indirect evidence for a delayed (type iv) cell type GN - lymphocytes from some patients with GN react in vitro with a glomerular Ag www.freelivedoctor.com
  67. 67. <ul><li>once immune complexes localized w/in GBM </li></ul><ul><li>other secondary affects cause immune </li></ul><ul><li>mediated injury  mediators: </li></ul><ul><li>a) complement (C5b-C9; cytotoxic) </li></ul><ul><li>b) neutrophils (chemotaxis via C5a) </li></ul><ul><li>c) monocytes & macrophages </li></ul><ul><li>d) coagulation system </li></ul><ul><li>NEPHRITIC SYNDROME </li></ul><ul><li>hematuria </li></ul><ul><li>oliguria </li></ul><ul><li> BUN and creatinine </li></ul><ul><li>hypertension </li></ul><ul><li>proteinuria (< 3.5 g/day); ± edema </li></ul>www.freelivedoctor.com
  68. 68. www.freelivedoctor.com
  69. 69. <ul><li>Glomerulornephritis - - INFLAMMATORY </li></ul><ul><li>Acute GN (post infectious GN) </li></ul><ul><li>a) sudden onset of nephritic syndrome </li></ul><ul><li>b) diffuse hypercellularity og glomeruli </li></ul><ul><li>c) most often associated with </li></ul><ul><li>i) group A β -hemolytic streptococci </li></ul><ul><li>- S. pyogenes </li></ul><ul><li>ii) others less frequently </li></ul><ul><li>- staph </li></ul><ul><li>- spirochetes </li></ul><ul><li>- viruses </li></ul><ul><li>d) most often affect children </li></ul><ul><li>i) one of most common renal diseases </li></ul>www.freelivedoctor.com
  70. 70. e) latent period of ~ 10-14 days f) diffuse enlargement and hypercellularity of glomeruli, hypercellularity due to: i) proliferation of endothelial and mesangial cells and infiltration of neutrophils and monocytes g) characteristics: i) subepithelial “humps” of GBM ii) granular IgG and C3 along GBM in association with “humps” h) Clinical: i) most resolve but in rare occasions can progress to develop many crescents and renal failure www.freelivedoctor.com
  71. 71. Acute GN (post infectious GN) www.freelivedoctor.com
  72. 72. <ul><li>ii) primary infection in pharynx or skin </li></ul><ul><li>iii) nephritic syndrome (abrupt) </li></ul><ul><li>- hematuria </li></ul><ul><li>- oliguria </li></ul><ul><li>- facial edema </li></ul><ul><li>- hypertension </li></ul><ul><li>iv)  serum C3 </li></ul><ul><li>Membranoproliferative GN </li></ul><ul><li>a) characterized by GBM thickening (i.e., “membrano”) + mesangial cell proliferation (“proliferative ”) </li></ul>www.freelivedoctor.com
  73. 73. b) two major groups: Types I and II (+ III) i) Type I: majority of cases are idiopathic. Associations with - HBV - HCV - bacterial endocarditis - strep infections - granular deposition of Ig (IgG, IgM) and complement (C3) and C1q and C4 ii) type II (and III) - circulating C3 Ab (C3 nephritic factor)   C3 (hypocomplementemia) www.freelivedoctor.com
  74. 74. - characteristic “ribbon-like” zone of  cellularity on thickened GBM (“dense deposit disease”) c) Clinical: i) occurs primarily in older children and young adults ii) nephritic or nephrotic syndrome iii) low levels of C3 iv) do not have postinfectious GN v) no systemic inflammatory condition vi) most progress to end-stage renal failure, regardless of treatment !! www.freelivedoctor.com
  75. 75. Membranoproliferative GN Type I www.freelivedoctor.com
  76. 76. <ul><li>SLE (immune complex disease); “Lupus </li></ul><ul><li>Nephritis” </li></ul><ul><li>a) chronic autoimmune disorder </li></ul><ul><li>b) affects 1  young women </li></ul><ul><li>c) > 70% will develop renal disease </li></ul><ul><li>d) circulating anti DNA Ab and  C3, etc. </li></ul><ul><li>i) T cell function is decreased </li></ul><ul><li>ii) trapping of immune complexes cause of the renal damage ( in situ ) </li></ul><ul><li>e) nephritic or nephrotic syndrome </li></ul><ul><li>f) dysfunction of renal tubules (usually accompanies GN) </li></ul><ul><li>g) cellular proliferation is mesangial, subepithelial and subendothelial cells </li></ul>www.freelivedoctor.com
  77. 77. i) involves the glomeruli w/more severe inflammation h) hematoxylin bodies  only light microscopic feature of tissue damage i) episodic inflammation – usually present with old lesions j) IgG most common. IgA and IgM also present. Complement present i) IgG, IgA, IgM, C3, C4 and C1q present in same glomerulus “FULL HOUSE” www.freelivedoctor.com
  78. 78. k) 5 classes based on WHO classification i) Class I – histologically normal ii) Class II – pure mesangial lesion iii) Class III – focal and segmental GN iv) Class IV – diffuse proliferative GN v) Class V – diffuse membranous - Class II and V have more benign course relative to Class III and IV l) renal disease  major consequence of SLE i) renal failure  cause of death in ~ 33 % of patients with SLE www.freelivedoctor.com
  79. 79. <ul><li>Focal GN </li></ul><ul><li>a) only some of the glomeruli are involved </li></ul><ul><li>i) or to segments of the glomerulus </li></ul><ul><li>b) different from focal & segmental glomerulosclerosis which is a noninflammatory disease </li></ul><ul><li>i) glomeruli essentially normocellular </li></ul><ul><li>c) many conditions produce this defect </li></ul><ul><li>i) primary renal disease or systemic diseases such as IgA nephropathy and Henoch-Schönlein GN (see table) </li></ul>www.freelivedoctor.com
  80. 80. d) IgA nephropathy (Berger Disease) i) association with chronic liver disease - impaired capacity to remove circulating immune complexes ii) IgA and fibronectin found in > 70 % of IgA nephropathy patients. iii) Ag involve bacterial, viral and dietary - infectious agents is suggested from data showing hematuria following upper respiratory or GI infection !! - dietary agents  milk proteins I in mesangium; gluten-sensitivity www.freelivedoctor.com
  81. 81. iv) C3 and properdin (via activation of alternate pathway) usually present together with IgA in mesangium - C1q and C4 (classic pathway activation) are typically absent v) IgA nephropathy is a mesangial proliferative lesion (granular deposits) vi) clinical - common in young men (15-30) - presents with hematuria - nephrotic type proteinuria is uncommon (may indicate more severe glomerular damage) www.freelivedoctor.com
  82. 82. - ~ 20 % of IgA nephropathy patients progress to end-stage renal failure !! - most common type of 1  GN in several parts of the world (France, Italy, Japan, Singapore and Austria) -- ~ 20 %. In USA is responsible for ~ 3-10 % of 1  GN www.freelivedoctor.com
  83. 83. IgA nephropathy (Berger Disease) www.freelivedoctor.com
  84. 84. <ul><li>e) Henoch-Schönlein (HS) Purpura </li></ul><ul><li>i) close relationship with IgA nephropathy </li></ul><ul><li>- differentiate: IgA purely renal; HS is a systemic disease, etc. </li></ul><ul><li>Crescentic GN </li></ul><ul><li>a) ominous morphological pattern </li></ul><ul><li>i) majority of glomeruli are surrounded </li></ul><ul><li> by accumulation of cells in Bowman’s capsule (parietal epithelial cells) </li></ul><ul><li>ii) indicative of fulminant glomerular damage and always leaves scarring </li></ul>www.freelivedoctor.com
  85. 85. iii) does not denote a specific etiologic form of GN b) most patients with substantial (~ 80%) crescents progress to renal failure c) Fibrin in Bowman’s capsule is important for the formation of glomerular crescents i) Tx with anticoagulants d) associated with areas of segmental necrosis within glomeruli e) Types: i) Type I – anti-GBM antibody disease (GOODPASTURE SYNDROME) or idiopathic www.freelivedoctor.com
  86. 86. - plasmapheresis to remove circulating Ab is helpful in this type of RPGN (i.e., crescentic) - etiology unknown ii) Type II – immune-complex mediated disease - can be complication of any of the immune complex nephritides  SLE, IgA nephropathy,  HS Purpura  all these show granular pattern (characteristic of immune complex) - not helped with plasmapheresis www.freelivedoctor.com
  87. 87. iii) Type III – pauci-immune type - lack of anti-GBM Ab or immune complexes - patients do have ANCA (~90%)  either c or p patterns } in some cases, is a component of vasculitides (i.e., Wegener Granulomatosis) f) clinical: i) hematuria with red cell cast in urine ii) transplant or chronic dialysis in most patients www.freelivedoctor.com
  88. 88. Crescentic GN www.freelivedoctor.com
  89. 89. <ul><li>TUBULOINTERSTITIAL DISEASE </li></ul><ul><li>Most tubular diseases involve the interstitium </li></ul><ul><li>2 distinct types of diseases </li></ul><ul><li>a) ischemic or toxic tubular injury  </li></ul><ul><li>i) ATN </li></ul><ul><li>ii) acute renal failure </li></ul><ul><li>b) inflammatory diseases </li></ul><ul><li>i) “tubulointerstitial nephritis” </li></ul><ul><li>ATN (Clinical entity) </li></ul><ul><li>Destruction of tubular epithelial cells </li></ul><ul><li>Acute suppression of renal function </li></ul>www.freelivedoctor.com
  90. 90. <ul><li>Most common cause of acute renal failure: </li></ul><ul><li>a) oliguria (, 400 ml/day) </li></ul><ul><li>b) severe glomerular disease (RPGN </li></ul><ul><li>c) acute thrombotic angioplasties </li></ul><ul><li>d) diffuse renal vascular disease (Polyarteritis nodosa) </li></ul><ul><li>e) diffuse cortical necrosis </li></ul><ul><li>f) interstitial nephritis (acute drug- induced) </li></ul><ul><li>g) acute papillary necrosis </li></ul>www.freelivedoctor.com
  91. 91. <ul><li>Is reversible and arise from: </li></ul><ul><li>a) severe trauma </li></ul><ul><li>b) septicemia (shock and hypotension) </li></ul><ul><li>c) ATN associated with shock – “ischemic” - d) mismatched blood transfusion and other hemodynamic problems as well as myoglobinuria  all reversible ischemic </li></ul><ul><li> ATN </li></ul><ul><li>e) nephrotoxic ATN – variety of poisons </li></ul><ul><li>i) - heavy metals (Hg) </li></ul><ul><li>ii) - CCl4 </li></ul><ul><li>iii) - etc. </li></ul>www.freelivedoctor.com
  92. 92. <ul><li>Occurs frequently </li></ul><ul><li>a) since it is reversible, proper management means difference between recovery and death </li></ul><ul><li>2 major problems are: </li></ul><ul><li>a) - tubular injuries </li></ul><ul><li>b) - blood flow disturbances </li></ul><ul><li>Major disturbances: </li></ul><ul><li>a) Change charge in tubules (mainly -) </li></ul><ul><li>i) Na+ - K+ - ATPase cause </li></ul><ul><li> less Na+ reabsorption and traps Na+, within tubule with more distal tube delivery of Na+ which causes </li></ul><ul><li> vasoconstriction (feedback) </li></ul>www.freelivedoctor.com
  93. 93. <ul><li>Treatment protocol </li></ul><ul><li>1) - initiating phase </li></ul><ul><li>2) - maintenance phase </li></ul><ul><li>3) - recovery phase </li></ul><ul><li>Initiating phase </li></ul><ul><li>Last about 36 hours. Incited by: </li></ul><ul><li>a) medical, surgical, obstetric event </li></ul><ul><li>i) slight oliguria (transient decrease in blood flow) </li></ul><ul><li>ii) rise in BUN </li></ul>www.freelivedoctor.com
  94. 94. <ul><li>Maintenance phase </li></ul><ul><li>Anywhere from 2-6 days </li></ul><ul><li>a) sharp decline in urine output (50-400 ml/day) </li></ul><ul><li>i) may last few days to 3 weeks </li></ul><ul><li>b) fluid overload, uremia </li></ul><ul><li>c) may die from poor management </li></ul><ul><li>Recovery phase </li></ul><ul><li>Steady increase in urine output (up to 3L/day) </li></ul><ul><li>Electrolyte imbalances may continue </li></ul><ul><li>Increased vulnerability to infection </li></ul><ul><li>Because of these, about 25% patients die in </li></ul><ul><li>this phase </li></ul>www.freelivedoctor.com
  95. 95. <ul><li>Tubulointerstitial Nephritis (TIN) </li></ul><ul><li>Inflammatory disease of Interstitium/tubules </li></ul><ul><li>Glomerulus not involved at all or only late in </li></ul><ul><li>disease </li></ul><ul><li>Infections induced TIN – “pyelonephritis” </li></ul><ul><li>Non infection – interstitial nephritis </li></ul><ul><li>a) Caused by: </li></ul><ul><li>i) drugs </li></ul><ul><li>ii) metabolic disorders (hypokalemia) </li></ul><ul><li>iii radiation injury </li></ul><ul><li>iv) immune reactions </li></ul>www.freelivedoctor.com
  96. 96. <ul><li>TIN divided into 2 categories, regardless of etiology </li></ul><ul><li>a) - acute </li></ul><ul><li>b) - chronic </li></ul><ul><li>Acute Pyelonephritis </li></ul><ul><li>Kidney/renal pelvis (distal to collecting ducts) </li></ul><ul><li>Caused by bacterial infections (lower UTI) – </li></ul><ul><li>cystitis, urethritis and prostatitis or upper UTI – </li></ul><ul><li>(pyelonephritis) or both tracts </li></ul><ul><li>Principle causative bacteria are gram - rods </li></ul><ul><li>a) E. coli (most common), Proteus, enterobacter, Klebsiella </li></ul>www.freelivedoctor.com
  97. 97. <ul><li>2 routes bacteria can reach kidney </li></ul><ul><li>a) blood stream (not very common) </li></ul><ul><li>b) lower urinary tract (ascending infections) </li></ul><ul><li>i) - catheterization </li></ul><ul><li>ii) - cystoscopy </li></ul><ul><li>Most commonly affect females (in absence of </li></ul><ul><li>instrumentation) </li></ul><ul><li>a) close proximity to rectum </li></ul><ul><li>b) shorter urethra </li></ul><ul><li>Urine sterile, flushing keeps bladder sterile </li></ul><ul><li>a) Obstruction increased incidence of UTI </li></ul><ul><li>i) prostate hypertrophy </li></ul><ul><li>ii) uterine prolapse </li></ul><ul><li>iii) UT obstructions </li></ul>www.freelivedoctor.com
  98. 98. <ul><li>Incompetent vesicoureteral orifice </li></ul><ul><li>a) one way valve (at level of bladder) </li></ul><ul><li>b) incompetence – reflux of urine into ureters – vesicoureteral reflux (VUR) – usually congenital defect – 30-50% of young children with UTI </li></ul><ul><li>c) - usually congenital defect </li></ul><ul><li>d) spinal cord injury can produce a flaccid bladder (residual volume remain in urinary tract) – favors bacterial growth </li></ul>www.freelivedoctor.com
  99. 99. <ul><li>e) Diabetes increases risk of serious complications </li></ul><ul><li>i) septicemia </li></ul><ul><li>ii) recurrence of infection </li></ul><ul><li>iii) diabetic neuropathy – dysfunction of bladder </li></ul><ul><li>f) pregnancy </li></ul><ul><li>i) 6% develop pyelonephritis; 40- 60% develop UTI if not treated </li></ul><ul><li>Chronic pyelonephritis and reflux nephropathy </li></ul><ul><li>Interstitial inflammation with scarring of renal </li></ul><ul><li>parenchyma </li></ul><ul><li>Important cause of chronic renal failure </li></ul>www.freelivedoctor.com
  100. 100. <ul><li>Two forms: </li></ul><ul><li>a) - Chronic obstructive pyelonephritis </li></ul><ul><li>b) - Chronic reflux-associated pyelonephritis </li></ul><ul><li>Chronic obstructive pyelonephritis </li></ul><ul><li>Can be bilateral (congenital disease) </li></ul><ul><li>Obstruction predisposes kidney to infection </li></ul><ul><li>recurrent infections on obstructive foci causes </li></ul><ul><li>scarring – chronic pyelonephritis! </li></ul>www.freelivedoctor.com
  101. 101. <ul><li>chronic reflux-associated pyelonephritis (reflux nephropathy) </li></ul><ul><li>More common form of chronic pyelonephritis scarring </li></ul><ul><li>Occurs from superimposed of a UTI on vesiculouretheral and intrarenal reflux </li></ul><ul><li>a) reflux may be bi- or unilateral </li></ul><ul><li>i) unilateral causes atrophy </li></ul><ul><li>ii) bilateral can cause chronic renal insufficiency </li></ul><ul><li>iii) diffuse or patchy </li></ul><ul><li>- Unclear if sterile vesiculouretheral disease causes renal damage </li></ul>www.freelivedoctor.com
  102. 102. <ul><li>Hallmark is scarring involving pelvis/calyces, leading to papillary blunting and deformities </li></ul><ul><li>Renal papilla – area of kidney where opening </li></ul><ul><li>from collecting ducts enters renal pelvis </li></ul><ul><li>Kidneys are asymmetrically contracted </li></ul><ul><li>Signs and Symptoms: </li></ul><ul><li>a) hypertension </li></ul><ul><li>b) seen following normal physical exam </li></ul><ul><li>c) slowly progressive  late in disease </li></ul><ul><li>d) can cause loss of concentrating mechanisms (if bilateral and progressive) </li></ul><ul><li>i) - polyuria </li></ul><ul><li>ii) - nocturia </li></ul>www.freelivedoctor.com
  103. 103. <ul><li>Drug-induced interstitial nephritis </li></ul><ul><li>Acute TIN – seen with synthetic penicillins, </li></ul><ul><li>diuretics (thiazides), NSAI </li></ul><ul><li>a) disease begins ~15 days (2-40 range) </li></ul><ul><li>i) fever </li></ul><ul><li>ii) rash (25% cases) </li></ul><ul><ul><li>iii) renal findings: hematuria, leukouria </li></ul></ul><ul><ul><li>iv) increased serum creatinine or acute renal failure with oliguria (50% of cases) </li></ul></ul><ul><li>Immune mechanism is indicated (suggested) </li></ul><ul><li>a) IgE increased (hypersensitivity – Type I) </li></ul><ul><li> Injury produced by IgE and cell-mediated immune reactions </li></ul>www.freelivedoctor.com
  104. 104. <ul><li>Analgesic Nephropathy </li></ul><ul><li>Patients who consume large quantities of </li></ul><ul><li>analgesics may develop chronic interstitial </li></ul><ul><li>nephritis , often associated with renal papillary </li></ul><ul><li>necrosis </li></ul><ul><li>Usually result from consumption of a mixture for </li></ul><ul><li>long periods of time: </li></ul><ul><li>a) - aspirin </li></ul><ul><li>b) - caffeine </li></ul><ul><li>c) - acetaminophen </li></ul><ul><li>d) - codeine </li></ul><ul><li>e) - phenacetin </li></ul>www.freelivedoctor.com
  105. 105. <ul><li>Primary pathogenesis is </li></ul><ul><li>a) papillary necrosis followed by </li></ul><ul><li>b) interstitial nephritis is secondary </li></ul><ul><li>c) acetaminophen – oxidative damage </li></ul><ul><li>d) aspirin inhibits prostaglandins – vasoconstriction </li></ul><ul><li>e) all the above leads to papillary ischemia </li></ul><ul><li>Chronic renal failure, hypertension and anemia </li></ul><ul><li>Complications may be incidence of “transitional </li></ul><ul><li>cell carcinoma” of renal pelvis or bladder. </li></ul>www.freelivedoctor.com
  106. 106. <ul><li>Diseases of Blood Vessels </li></ul><ul><li>Nearly all diseases of kidney involve blood </li></ul><ul><li>vessels. </li></ul><ul><li>Kidneys involved in pathogenesis of essential </li></ul><ul><li>and secondary hypertension </li></ul><ul><li>Systemic vascular disease (i.e. arteritis) also </li></ul><ul><li>involve kidney </li></ul>www.freelivedoctor.com
  107. 107. <ul><li>Benign nephrosclerosis </li></ul><ul><li>Renal changes associated with benign </li></ul><ul><li>hypertension </li></ul><ul><li>a) always associated with hyaline arteriosclerosis </li></ul><ul><li>Kidneys are atrophic </li></ul><ul><li>Many renal diseases cause hypertension which </li></ul><ul><li>in turn may lead to benign nephrosclerosis. </li></ul><ul><li>Therefore this disease seen simultaneously </li></ul><ul><li>with other diseases of kidney </li></ul>www.freelivedoctor.com
  108. 108. <ul><li>This disease by itself usually does not cause </li></ul><ul><li>severe damage </li></ul><ul><li>a) mild oliguria </li></ul><ul><li>b) loss (slight) of concentrating mechanism </li></ul><ul><li>c) decreases GFR </li></ul><ul><li>d) mild degree of proteinuria is a constant finding </li></ul><ul><li>These patients usually die from hypertensive </li></ul><ul><li>heart disease or cerebrovascular disease rather </li></ul><ul><li>than from renal disease </li></ul>www.freelivedoctor.com
  109. 109. <ul><li>Malignant hypertension </li></ul><ul><li>Less common than benign </li></ul><ul><li>May arise de novo (without preexisting </li></ul><ul><li>hypertension) or may arise suddenly in patient </li></ul><ul><li>with mild hypertension </li></ul><ul><li>Factors: </li></ul><ul><li>a) initial event – some form of vascular </li></ul><ul><li>damage to kidney </li></ul><ul><li>b) result is increased permeability of small blood vessels to fibrinogen and other plasma proteins, endothelial injury </li></ul><ul><li> and platelet deposits </li></ul>www.freelivedoctor.com
  110. 110. c) This leads to appearance of fibroid necrosis in small arteries and arterioles and intravascular thrombosis d) platelets (platelet derived growth factors) and plasma cause intimal hyperplasia of vessels resulting in hyperplastic arteriosclerosis, which is typical of malignant hypertension e) narrowing of renal afferent arteriole stimulates angiotensin II production (ischemic-induced) with aldosterone secretion increases www.freelivedoctor.com
  111. 111. <ul><li>Diastolic pressure > 120 mmHg, papilledema, </li></ul><ul><li>encephalopathy, CV disorders, renal failure </li></ul><ul><li>90% deaths due to uremia </li></ul><ul><li>10% deaths due to CV or cerebral disorders </li></ul><ul><li>(hemorrhage) </li></ul>www.freelivedoctor.com
  112. 112. <ul><li>Thrombotic Microangiopathies </li></ul><ul><li>Clinical syndromes </li></ul><ul><li>Widespread thrombosis in microcirculation (a/C) </li></ul><ul><li>Damage to endothelial cells !! </li></ul><ul><li>Diseases: </li></ul><ul><li>a) childhood hemolytic-uremia syndrome </li></ul><ul><li>(HUS) </li></ul><ul><li>b) Thrombotic thrombocytopenic purpura </li></ul><ul><li>Most follow intestinal infection (E. Coli) </li></ul><ul><li>Disease is one of main causes of acute renal </li></ul><ul><li>failure in children </li></ul><ul><li>Vasoconstriction (decreased NO, increased </li></ul><ul><li>endothelium, decreased PGI 2 ) </li></ul>www.freelivedoctor.com
  113. 113. <ul><li>Although the various diseases have diverse </li></ul><ul><li>etiologies, 2 predominant factors  </li></ul><ul><li>a) endothelial injury and activation, leading to vascular thrombosis and, </li></ul><ul><li>b) platelet aggregation </li></ul><ul><li>c) both of these causing vascular obstruction and vasoconstriction </li></ul><ul><li>1.- Endothelial injury </li></ul><ul><li>activation can be initiated by a variety of </li></ul><ul><li>agents, while some remain elusive </li></ul><ul><li>a) denuding the endothelial cells, exposes vascular to thrombogenic subendothelium </li></ul><ul><li>i)  NO, PGI 2 , enhance platelet aggregation and vasoconstriction </li></ul>www.freelivedoctor.com
  114. 114. <ul><li>ii) vasoconstriction also initiated via endothelial derived endothelin-1 </li></ul><ul><li>iii) activation of endothelial cells increases adhesiveness to platelets, etc </li></ul><ul><li>iv) endothelial cells elaborate large multimers of vW factor  platelet aggregation </li></ul><ul><li>2.- Platelet Aggregation </li></ul><ul><li>serum factors causing platelet aggregation </li></ul><ul><li>a) large multimers of vW factor (secreted by endothelial cells) </li></ul><ul><li>i) usually cleaved by ADAMTS-13 (vW factor-cleaving metalloprotease </li></ul>www.freelivedoctor.com
  115. 115. <ul><li>HUS/TTP </li></ul><ul><li>1.- Classic childhood HUS (> 75%) </li></ul><ul><li>bloody diarrhea  intestinal infection </li></ul><ul><li>a) verocytotoxin-releasing bacteria </li></ul><ul><li>i) Verocytotoxin-producing strains of E. coli (eg 0157:H7 or 0103); </li></ul><ul><li>ii) Similar to Shigella toxin. </li></ul><ul><li>iii) undercooked hamburger </li></ul><ul><li>iv) “petting” zoos </li></ul>www.freelivedoctor.com
  116. 116. <ul><li>characterized: </li></ul><ul><li>a) sudden onset (post GI or influenza infection) </li></ul><ul><li>b) hematemesis </li></ul><ul><li>c) melena </li></ul><ul><li>d) severe oliguria </li></ul><ul><li>e) hematuria </li></ul><ul><li>f) hemolytic anemia (microangiopathic) </li></ul><ul><li>g) hypertension in > 50% of cases </li></ul>www.freelivedoctor.com
  117. 117. <ul><li>Pathogenesis </li></ul><ul><li>a) related to Shigella toxin </li></ul><ul><li>i) affects endothelium </li></ul><ul><li>-  adhesion of leukocytes </li></ul><ul><li>-  endothelin and  NO </li></ul><ul><li>- endothelial lysis (inpresence of cytokines such as TNF </li></ul><ul><li>ii) these changes favor thrombosis and vasoconstriction </li></ul><ul><li>iii) verocytotoxin can directly bind to platelets and cause activation </li></ul><ul><li>most patients recover in few weeks, with </li></ul><ul><li>proper care (i.e., dialysis, etc); < 5% lethality </li></ul>www.freelivedoctor.com
  118. 118. <ul><li>2.- Adult HUS </li></ul><ul><li>associated with: </li></ul><ul><li>a) infection </li></ul><ul><li>i) typhoid fever </li></ul><ul><li>ii) E. coli septicemia </li></ul><ul><li>iii) etx or shiga toxin </li></ul><ul><li>iv) viral infections </li></ul><ul><li>b) antiphospholipid syndrome </li></ul><ul><li>i) SLE </li></ul><ul><li>ii) similar to membranoproliferative GN but w/out immune complex deposits </li></ul><ul><li>c) complication of pregnancy (“postpartum renal failure” </li></ul>www.freelivedoctor.com
  119. 119. <ul><li>d) vascular renal disease </li></ul><ul><li>i) systemic sclerosis </li></ul><ul><li>ii) malignant hypertension </li></ul><ul><li>e) chemotherapeutic and immunosuppressive drugs </li></ul><ul><li>i) mitomycin </li></ul><ul><li>ii) cyclosporine </li></ul><ul><li>iii) bleomycin </li></ul><ul><li>iv) cisplatin </li></ul><ul><li>v) radiation Tx </li></ul><ul><li>3.- Familial HUS </li></ul><ul><li>recurrent thromboses (~ 50 lethality) </li></ul><ul><li>deficit of complement regulatory protein </li></ul><ul><li>a) Factor H </li></ul>www.freelivedoctor.com
  120. 120. <ul><li>4.- Idiopathic Thrombotic Thrombocytopenic Purpura </li></ul><ul><li>Manifested by: </li></ul><ul><li>a) thrombi in glomeruli </li></ul><ul><li>b) fever </li></ul><ul><li>c) hemolytic anemia </li></ul><ul><li>d) neurologic symptoms </li></ul><ul><li>e) thrombocytopenic purpura </li></ul><ul><li>defect in ADAMTS-13 (acquired or inherited) </li></ul><ul><li>a) normally cleaves large vW multimers </li></ul><ul><li>i) large vW factors promote platelet aggregation </li></ul><ul><li>more common in women </li></ul><ul><li>most patients < 40 years </li></ul>www.freelivedoctor.com
  121. 121. <ul><li>neurologic involvement is dominant feature </li></ul><ul><li>renal involvement in ~ 50% of patients </li></ul><ul><li>a) eosinophilic thrombi in glomerular capillaries, interlobular artery and afferent arterioles </li></ul><ul><li>b) similar changes as with HUS </li></ul><ul><li>exchange transfusion and steroid Tx  </li></ul><ul><li>mortality rate to < 50% </li></ul>www.freelivedoctor.com
  122. 122. <ul><li>Cystic Diseases </li></ul><ul><li>Common and difficult to diagnose </li></ul><ul><li>In adult polycystic disease – major cause of </li></ul><ul><li>chronic renal failure </li></ul><ul><li>Confused with malignant tumors </li></ul><ul><li>Simple cyst </li></ul><ul><li>a) Innocuous lesion </li></ul><ul><li>b) Occur as single or multiple cysts </li></ul><ul><li>c) Usually 1-5 cm diameter </li></ul><ul><li>d) Clear fluid, smooth membrane, gray </li></ul><ul><li>glistening </li></ul>www.freelivedoctor.com
  123. 123. <ul><li>e) Single layer of cuboidal cells </li></ul><ul><li> f) Usually confined to cortex </li></ul><ul><li> g) No clinical significance </li></ul><ul><li>Importance to differentiate from tumors </li></ul><ul><li>a) are fluid filled rather than solid </li></ul><ul><li>b) have smooth contours </li></ul><ul><li>c) almost always avascular </li></ul><ul><li>Occur in patients with end-stage renal disease </li></ul><ul><li>who have undergone long term dialysis </li></ul><ul><li>Occasionally, renal adenomas or adenosarcoma </li></ul><ul><li>arise from these cysts </li></ul>www.freelivedoctor.com
  124. 124. <ul><li>Adult polycystic kidney disease (autosomal dominant) </li></ul><ul><li>Multiple expanding cysts of both kidneys that </li></ul><ul><li>eventually destroy parenchyma of kidney </li></ul><ul><li>Accounts for 10% of chronic renal failure </li></ul><ul><li>In 90% of families, PKD1 (defective gene) is </li></ul><ul><li>located on chromosome #16 </li></ul><ul><li>a) encodes for protein (polycystin-1), extracellular and is a cell membrane associated protein </li></ul><ul><li>b) how mutations in this gene cause cysts formation is unclear </li></ul>www.freelivedoctor.com
  125. 125. <ul><li>Polycystin 2 (PKD2 gene) mutations also cause </li></ul><ul><li>cyst formation </li></ul><ul><li>No symptoms until 4th decade </li></ul><ul><li>a) by then, kidneys are very large </li></ul><ul><li>b) common complaint is “flank pain” </li></ul><ul><li>c) hematuria </li></ul><ul><li>d) most important complications </li></ul><ul><li>i) hypertension (~75% patients) </li></ul><ul><li>ii) UTI </li></ul><ul><li>iii) aneurysms in circle of Willis (10- 30%) and risk for subarachnoid hemorrhage </li></ul>www.freelivedoctor.com
  126. 126. <ul><li>iv) Asymptomatic liver cysts in ~30- 40% </li></ul><ul><li>v) fatal disease (uremia or hypertension) </li></ul><ul><li>vi) progresses very slowly </li></ul><ul><li>viii) Treatment with renal transplantation </li></ul><ul><li>Childhood polycystic kidney disease (autosomal recessive) </li></ul><ul><li>Rare </li></ul><ul><li>Serious manifestations at birth and young </li></ul><ul><li>infants may die quickly </li></ul><ul><li>a) pulmonary failure </li></ul><ul><li>b) renal failure </li></ul>www.freelivedoctor.com
  127. 127. <ul><li>Numerous small cysts in cortex and medulla </li></ul><ul><li>Bilateral disease </li></ul><ul><li>Many epithelial cysts in liver </li></ul><ul><li>Patients who survive infancy develop liver </li></ul><ul><li>cirrhosis (congenital hepatic cirrhosis) </li></ul><ul><li>Unidentified gene location on chromosome 6p </li></ul><ul><li>Urinary Outflow-Obstruction </li></ul><ul><li>Renal Stones </li></ul><ul><li>Urolithiasis: Calculus formation at any level in urine collecting system, most often arise in kidney </li></ul>www.freelivedoctor.com
  128. 128. <ul><li>Occur frequently (!1% of all autopsies) </li></ul><ul><li>More common in males </li></ul><ul><li>Familial tendency </li></ul><ul><li>~75% of renal stone </li></ul><ul><li>a) calcium oxalate </li></ul><ul><li>b) calcium phosphate </li></ul><ul><li>15% composed of magnesium ammonium </li></ul><ul><li>phosphate </li></ul><ul><li>10% uric acid or cystine stones </li></ul><ul><li>All stones composed of mucoprotein </li></ul>www.freelivedoctor.com
  129. 129. <ul><li>Cause of stones is obscure </li></ul><ul><li>a) Supersaturation in urine of stones constituents (exceeds solubility) </li></ul><ul><li>b) 50% of patients forming “calcium stones” do not have increased plasma Ca ++ but do have high urine Ca ++ </li></ul><ul><li>i) most Ca ++ absorbed from gut in large amounts (absorptive hypercalciuria) </li></ul><ul><li>ii) only 5-10% has associated hypercalcemia </li></ul>www.freelivedoctor.com
  130. 130. <ul><ul><li>- hyperparathyroidism </li></ul></ul><ul><ul><li>- Vit D intoxication </li></ul></ul><ul><ul><li>- Sarcoidosis (autoimmune disease, bacterial </li></ul></ul><ul><li>- productions of Vit D (toxic) </li></ul><ul><li>c) Magnesium ammonium Phosphate stones </li></ul><ul><li>i) almost always occur in patients with alkaline urine due to UTI </li></ul><ul><li>ii) proteus vulgaris and staph split urea in kidney and therefore predispose patient to urolithiasis </li></ul>www.freelivedoctor.com
  131. 131. <ul><li>Gout and diseases involved with rapid cell </li></ul><ul><li>turnover (e.g. leukemia) lead to high uric acid </li></ul><ul><li>levels in urine and possibility of uric acid stones </li></ul><ul><li>Unlike magnesium ammonium phosphate stone, </li></ul><ul><li>both uric acid and cystine stones are more </li></ul><ul><li>likely to form when urine is acidic (pH < 5.5) </li></ul><ul><li>Stone formation 80% unilateral </li></ul><ul><li>Hematuria and predispose to infection </li></ul>www.freelivedoctor.com
  132. 132. <ul><li>Hydronephrosis </li></ul><ul><li>Dilation of renal pelvis and calyces with atrophy </li></ul><ul><li>of parenchyma caused by obstruction of outflow </li></ul><ul><li>of urine </li></ul><ul><li>Most common causes: </li></ul><ul><li>a) congenital </li></ul><ul><li>i) atresia of the urethra (absence of a normal body passage or opening from an organ to other parts of the body) </li></ul>www.freelivedoctor.com
  133. 133. <ul><li>b) acquired </li></ul><ul><li>i) stones </li></ul><ul><li>ii) tumors </li></ul><ul><li>iii) inflammation </li></ul><ul><li>iv) spinal cord damage with paralysis of bladder </li></ul><ul><li>v) normal pregnancy </li></ul><ul><li>Bilateral nephrons only if blockage is below </li></ul><ul><li>level or ureters </li></ul><ul><li>Major problems are tubular with impaired </li></ul><ul><li>concentration mechanisms </li></ul><ul><li>Obstruction leads to inflammatory response a) interstitial fibrosis </li></ul><ul><li>Complicating pyelonephritis is common </li></ul>www.freelivedoctor.com
  134. 134. <ul><li>Tumors </li></ul><ul><li>Most common malignant tumor is: </li></ul><ul><li>a) renal cell carcinoma (80-85% of all 1° Ca in kidney) </li></ul><ul><li>b) nephroblastoma (Wilms tumor) </li></ul><ul><li>c) calyces and pelvis </li></ul><ul><li>Tumor of lower urinary tract are 2x as common </li></ul><ul><li>as renal cell Cancer </li></ul><ul><li>1.- Renal cell Ca </li></ul><ul><li>Derived from renal tubular epithelial cells </li></ul><ul><li>a) located primarily in cortex </li></ul><ul><li>2-3% of all cell Ca in adults (~30,000 cases/yr) </li></ul><ul><li>6th to 7th decades in life </li></ul>www.freelivedoctor.com
  135. 135. <ul><li>Higher risk in smokers and occupational </li></ul><ul><li>exposure to cadmium </li></ul><ul><li>30 fold increase in susceptibility in patients with </li></ul><ul><li>polycystic disease </li></ul><ul><li>Classification: </li></ul><ul><li>a) clear cell Cancer </li></ul><ul><li>i) most common (70-80% renal ca) </li></ul><ul><li>b) most are sporadic </li></ul><ul><li>c) familial links (von Hippel-Lindau [VHL]) </li></ul><ul><li>i) autosomal dominant disease </li></ul><ul><li>ii) predispose to a variety of CA – hemangioblastoma of cerebellum and retina </li></ul>www.freelivedoctor.com
  136. 136. <ul><li>iii) genetic abnormality chromosome 3 (loss of tumor suppressor gene) – clear cell CA </li></ul><ul><li>2.- Papillary renal cell Ca </li></ul><ul><li>10-15% of all renal CA </li></ul><ul><li>Multifocal and bilateral </li></ul><ul><li>Both sporadic and familial forms </li></ul><ul><li>No genetic abnormalities in chromosome 3 </li></ul><ul><li>a) Protooncogene on chromosome 7 </li></ul>www.freelivedoctor.com
  137. 137. <ul><li>3- Chromophobe Renal Carcinoma </li></ul><ul><li>Least common (~5% of all renal cell CA) </li></ul><ul><li>Cortical collecting ducts or their collated cells </li></ul><ul><li>Stain more darkly than clear cell CA </li></ul><ul><li>Lack of a lot of chromosomes (1,2,6,10,17,&21) </li></ul><ul><li>Have good prognosis </li></ul><ul><li>Renal cell CA are difficult to diagnose! </li></ul><ul><li>a) Present with hematuria in ~50% of cases </li></ul><ul><li>4. Wilms tumor </li></ul><ul><li>Occurs infrequently in adults </li></ul><ul><li>1/3 most common organ cancer in children <10 years, therefore, one of major cancers in children </li></ul><ul><li>Sporadic or familial in nature </li></ul><ul><li>a) autosomal dominant </li></ul>www.freelivedoctor.com
  138. 138. <ul><li>Urinary bladder and collecting system tumors (Renal pelvis to urethra) </li></ul><ul><li>Tumors in collecting system above bladder are </li></ul><ul><li>uncommon </li></ul><ul><li>Bladder Cancer more frequent cause of death </li></ul><ul><li>than are kidney tumors </li></ul><ul><li>a) Bladder tumors </li></ul><ul><li>i) small benign papillomas (rare) </li></ul><ul><li>ii) large invasive CA </li></ul><ul><li>iii) most recur after removal and kill by infiltrative obstruction of ureters rather than by metastasizing </li></ul><ul><li>iv) Shallow lesion have good prognosis </li></ul>www.freelivedoctor.com
  139. 139. v) deep invasive Cancer, survival (5yr) is <20% with overall 5 yr survival at 50-60% b) - Cancer of ureters is very rare i) 5 yr survival <10% www.freelivedoctor.com
  140. 140. <ul><li>RENAL PATHOLOGY </li></ul><ul><li>Dr. Richard M Raymond </li></ul><ul><li>Diseases affect </li></ul><ul><li>a) glomeruli (often immunological) </li></ul><ul><li>b) tubules (toxic, infectious) </li></ul><ul><li>c) interstitium (toxic, infectious) </li></ul><ul><li>d) vascular </li></ul><ul><li>Disease in one area usually results in </li></ul><ul><li>damage or disease on neighboring areas </li></ul><ul><li>Large functional reserve </li></ul><ul><li>a) > 75% destruction before impairment </li></ul>www.freelivedoctor.com
  141. 141. <ul><li>Congenital Anomalies </li></ul><ul><li>Review page 961 , “Robbins and Cotran” PATHOLOGIC BASIS OF DISEASE . 7 TH ed. </li></ul><ul><li>Understand and describe the following </li></ul><ul><li>congenital anomalies of the kidney </li></ul><ul><li>a) agenesis </li></ul><ul><li>b) hypoplasia </li></ul><ul><li>c) ectopic kidney </li></ul><ul><li>d) horseshoe kidney </li></ul>www.freelivedoctor.com
  142. 142. <ul><li>GLOMERULI </li></ul><ul><li>Network of capillaries </li></ul><ul><li>a) lined by fenestrated endothelium </li></ul><ul><li>b) basement membrane </li></ul><ul><li>c) podocytes (“foot processes”) </li></ul><ul><li>Glomeruli capillary wall </li></ul><ul><li>a) lined with fenestrated endothelium ( 70- 100 nm) </li></ul><ul><li>b) glomerular basement membrane (GBM) </li></ul><ul><li>i) consist of collagen (type IV), heparan sulfate, laminin, glycoproteins </li></ul>www.freelivedoctor.com
  143. 143. - Type IV collagen forms network to which glycoprotein's attach c) visceral epithelial cells (podocytes; “foot processes”) i) composed of interdigitating processes embedded to basement membrane ii) adjacent foot processes are separated by 20-30 nm filtration slits bridged by thin diaphragm (nephrin) d) entire glomerulus is supported by mesangial cells i) lying between capillaries www.freelivedoctor.com
  144. 144. <ul><li>ii) phagocytic, contractile, proliferate, secretion of biologically active mediators </li></ul><ul><li>- modified smooth muscle cells </li></ul><ul><li>iii) involved in many types of GN </li></ul><ul><li>Glomeruli </li></ul><ul><li>a) very permeable to H 2 O and small solutes </li></ul><ul><li>b) impermeable to proteins (~ 70 kDa or larger; i.e., albumin) </li></ul><ul><li>c) “glomerular barrier function” </li></ul><ul><li>i) selective permeability based on: </li></ul><ul><li>- size </li></ul><ul><li>- charge: cationic more permeable </li></ul>www.freelivedoctor.com
  145. 145. ii) podocytes important in maintaining this “function” - slit diaphragm maintain size- selectivity by specific proteins 1.- NEPHRIN : extend towards each other from neighboring podocytes comprising the slit diaphragm !! 2.- PODOCIN : intracellular (podocyte) protein where nephrin attaches - mutations in genes encoding these proteins give rise to nephrotic syndrome (i.e., glomerular disease) www.freelivedoctor.com
  146. 146. www.freelivedoctor.com
  147. 147. www.freelivedoctor.com
  148. 148. www.freelivedoctor.com
  149. 149. www.freelivedoctor.com
  150. 150. <ul><li>Clinical Manifestations </li></ul><ul><li>Termimology </li></ul><ul><li>a) Azotemia :  BUN and  creatinine </li></ul><ul><li>i) related to  GFR </li></ul><ul><li>- prerenal azotemia:  RBF, hypoperfusion w/out parenchymal damage </li></ul><ul><li>- postrenal azotemia: obstruction of urine flow below level of kidney </li></ul>www.freelivedoctor.com
  151. 151. <ul><li>b) when azotemia becomes associated with a variety of clinical S & S and biochemical abnormalities  UREMIA </li></ul><ul><li>Major Renal Syndromes </li></ul><ul><li>a) Nephritic syndrome : glomerular disease, hematuria, mild  moderate proteinuria, azotemia, edema,  BP </li></ul><ul><li>i) classic presentation of post streptococcal GN </li></ul><ul><li>b) Nephrotic syndrome : heavy proteinuria (> 3.5 g/day), hypoalbuminemia, severe edema, hyperlipidemia and lipiduria </li></ul>www.freelivedoctor.com
  152. 152. c) Acute renal failure : oliguria/anuria, recent onset of azotemia, can result from GN, tubular or interstitial disease d) Nephroliathiasis : renal stones, renal colic, hematuria, recurrent stone formation e) Chronic renal failure : 4 stages i)  renal reserve: GFR ~ 50% normal BUN & creatinine normal, pt. asymptomatic, more susceptible to develop azotemia ii) renal insufficiency: GFR 20-50% of normal, azotemia, anemia,  BP, polyuria/nocturia (via  concentrating ability) www.freelivedoctor.com
  153. 153. iii) renal failure : GFR less than 20-25% kidneys cannot regulate volume, ions: edema, hypocalcemia, metabolic acidosis, uremia with neurological, CV and GI complications iv) end stage renal disease : GFR < 5% of normal, terminal stage of uremia www.freelivedoctor.com
  154. 154. www.freelivedoctor.com
  155. 155. <ul><li>Glomerular Disease </li></ul><ul><li>Chronic GN one of most common causes </li></ul><ul><li>of chronic renal failure </li></ul><ul><li>Glomerular disease often associated with </li></ul><ul><li>systemic disorders such as: </li></ul><ul><li>a) diabetes mellitus </li></ul><ul><li>b) SLE </li></ul><ul><li>c) amyloidosis </li></ul><ul><li>d) vasculitis </li></ul><ul><li>- pts. with manifestations of glomerular disease should be considered for these systemic syndromes, etc. </li></ul>www.freelivedoctor.com
  156. 156. <ul><li>GN characterized by one or more of the </li></ul><ul><li>following (inflammatory diseases of </li></ul><ul><li>glomerulus) </li></ul><ul><li>a) hypercellularity : </li></ul><ul><li>i) cell proliferation of mesangial cells or endothelial cells </li></ul><ul><li>ii) leukocyte infiltration (neutrophils, monocytes and sometimes lymphocytes) </li></ul><ul><li>iii) formation of crescents </li></ul><ul><li>- epithelial cell proliferation (from immune/inflammatory injury) </li></ul><ul><li>- fibrin thought to elicit this injury (TNF, IL-1, IFN-  are others) </li></ul>www.freelivedoctor.com
  157. 157. b) basement membrane thickening i) deposition of immune complexes on either the endothelial or epithelial side of GBM or w/in GBM itself ii) thickening of GBM proper as with diabetes mellitus (diabetic glomerulosclerosis) c) hyalinization (hyalinosis) and sclerosis i) accumulation of material that is eosinophilic and homogeneous - obliterates capillary lumen of glomerulus (sclerotic feature) www.freelivedoctor.com
  158. 158. <ul><li>- result of capillary or endothelial injury. Usually end result of various forms of glomerular damage (intraglomerular thromboses, accumulation of other metabolic materials) </li></ul><ul><li>Since etiology of primary GN is unknown, </li></ul><ul><li>classification is based on histology. </li></ul><ul><li>Subdivided: </li></ul><ul><li>a) diffuse (all glomeruli) </li></ul><ul><li>b) global (entire glomerulus) </li></ul><ul><li>c) focal (portion of glomeruli) </li></ul><ul><li>d) segmental (part of each glomerulus) </li></ul><ul><li>e) mesangial (affecting mesangial region) </li></ul>www.freelivedoctor.com
  159. 159. <ul><li>Pathogenesis of Glomerular Disease/Injury </li></ul><ul><li>Little is known regarding etiology or </li></ul><ul><li>triggering </li></ul><ul><li>Immune mechanisms underlie most </li></ul><ul><li>cases of primary GN and many of the </li></ul><ul><li>secondary cases </li></ul><ul><li>a) 2 forms of Ab-associated injury </li></ul><ul><li>i) injury resulting from soluble Ag-Ab deposits in glomerulus </li></ul><ul><li>ii) injury from Ab reacting in-situ with glomerulus </li></ul><ul><li>- insoluble fixed glomerular Ag </li></ul><ul><li>- molecules planted w/in glomerulus </li></ul>www.freelivedoctor.com
  160. 160. <ul><li>Examples </li></ul><ul><li>In Situ Immune Complex Deposition </li></ul><ul><li>a) Ab act directly with intrinsic tissue Ag </li></ul><ul><li> “ planted” in the glomerulus from the circulation </li></ul><ul><li>b) 2 forms of Ab-mediated glomerular injury </li></ul><ul><li>i) anti-GBM Ab-induced nephritis </li></ul><ul><li>- Ab directed against fixed Ag in GBM </li></ul><ul><li>- in humans spontaneous AGBM nephritis is autoimmune disease </li></ul>www.freelivedoctor.com
  161. 161. - Ab bind along GBM forming a “linear pattern” - sometimes AGBM Ab cross react with BM of lung  GOODPASTURE SYNDROME - < 1% of GN cases - some cases show severe glomerular damage and rapidly progressive crescentic GN ii) Heymann nephritis - a form of membranous GN - Ab bind along GBM in “granular pattern” www.freelivedoctor.com
  162. 162. <ul><li>c) Trigger for induction of autoimmune Ab is </li></ul><ul><li> unclear </li></ul><ul><li>i) ETX </li></ul><ul><li>ii) mercuric chloride </li></ul><ul><li>iii) graft-vs.-host reaction </li></ul><ul><li>Ab can react with “planted” Ag in GBM </li></ul><ul><li>a) cationic Ag binding to anionic GBM sites </li></ul><ul><li>b) bacterial byproducts </li></ul><ul><li>c) IgG deposition in mesangium </li></ul>www.freelivedoctor.com
  163. 163. www.freelivedoctor.com
  164. 164. <ul><li>re: Ab-mediated injury  Ag-Ab deposition in GBM is major pathway of glomerular injury !! </li></ul><ul><li>a) largest proportion of cases of GN are granular immune pattern along the GBM or mesangium </li></ul><ul><li>Cell mediated immune GN </li></ul><ul><li>a) sensitized T cells can cause glomerular injury, in absence of immune deposits </li></ul><ul><li>i) may occur in some forms of rapidly progressive GN </li></ul>www.freelivedoctor.com
  165. 165. www.freelivedoctor.com
  166. 166. <ul><li>Mediators of immune injury </li></ul><ul><li>seen as loss of glomerular barrier function </li></ul><ul><li>a) proteinuria </li></ul><ul><li>b)  GFR in some instances </li></ul><ul><li>Complement-leukocyte mechanism </li></ul><ul><li>a) well established </li></ul><ul><li>i) activated complement (C5a)  </li></ul><ul><li> neutrophils and monocytes </li></ul><ul><li>- release proteases  degrade GBM </li></ul><ul><li>ii) ROS </li></ul><ul><li>iii) some are neutrophil-independent </li></ul><ul><li>- C5-C9 (lytic component; membrane attack complex) </li></ul>www.freelivedoctor.com
  167. 167. <ul><li>- Membrane attack complex stimulate growth factors (TGF)  GBM thickening </li></ul><ul><li>iv) direct cytotoxicity </li></ul><ul><li>Other mechanisms of glomerular injury </li></ul><ul><li>a) epithelial cell injury </li></ul><ul><li>i) can be induced by Ab to visceral epithelial cell Ag </li></ul><ul><li>ii) toxins </li></ul><ul><li>iii) cytokines </li></ul><ul><li>iv) loss of foot processes </li></ul><ul><li>- caused by alterations in nephrin </li></ul>www.freelivedoctor.com
  168. 168. b) renal ablation GN i) any renal disease   GFR (30-50% of normal) - lead to end stage renal failure ii) patients develop proteinuria and diffuse glomerulosclerosis - initiated by unaffected glomeruli  hypertrophy to maintain function  single nephron hypertension  damage www.freelivedoctor.com
  169. 169. <ul><li>Glomerular Syndromes and Disorders </li></ul><ul><li>Nephrotic Syndrome </li></ul><ul><li>a) massive proteinuria (> 3.5 g/day) </li></ul><ul><li>b) hypoalbuminemia </li></ul><ul><li>c) generalized edema </li></ul><ul><li>d) hyperlipidemia and lipiduria </li></ul><ul><li>Initial event is derangement of GBM  </li></ul><ul><li>increasing permeability and progressive </li></ul><ul><li>loss of plasma proteins  </li></ul><ul><li>hypoalbuminemia  decrease in plasma </li></ul><ul><li>colloid osmotic pressure  edema   </li></ul><ul><li>plasma volume   aldosterone </li></ul>www.freelivedoctor.com
  170. 170. <ul><li> ANP, GFR   water and solute retention by </li></ul><ul><li>kidney  exacerbation of edema (anasarca; </li></ul><ul><li>massive amounts of edematous fluid); </li></ul><ul><li>hypoalbuminemia   lipoprotein production </li></ul><ul><li>by the liver </li></ul><ul><li>In children < 15 yrs, nephrotic syndrome </li></ul><ul><li>almost always caused by primary renal </li></ul><ul><li>disease (~ 98 %) </li></ul><ul><li>In adults nephrotic syndrome may often </li></ul><ul><li>be associated with secondary renal </li></ul><ul><li>disease </li></ul>www.freelivedoctor.com
  171. 171. www.freelivedoctor.com
  172. 172. <ul><li>GLOMERULAR DISEASES </li></ul><ul><li>( NONINFLAMMATORY ) </li></ul><ul><li>Membranous Glomerulopathy (epithelial </li></ul><ul><li>cell and BM disease) </li></ul><ul><li>a) most common cause of nephrotic syndrome in adults (C5-C9 cytotoxic) </li></ul><ul><li>b) diffuse thickening of glomerular capillary wall !! </li></ul><ul><li>c) most cases are idiopathic </li></ul><ul><li>i) most believed to be autoimmune </li></ul><ul><li>d) most cells are normocellular or only mildly hypercellular </li></ul>www.freelivedoctor.com
  173. 173. e) believed to be caused by i) deposition of immune complexes w/in capillary wall - IgG and C3 ii) formation of in situ immune complexes iii) refer to Heymans nephritis and Goodpasture syndrome iv) classified as non inflammatory since there is NO cellular proliferation f) In adults, a frequent association is with carcinoma !! (i.e., melanoma, lung and colon) www.freelivedoctor.com
  174. 174. <ul><li>g) associated with systemic infections </li></ul><ul><li>i) HBV </li></ul><ul><li>ii) SLE </li></ul><ul><li>h) associated with certain drug treatments </li></ul><ul><li>i) gold, penicillamine, NSAID </li></ul><ul><li>Clinical </li></ul><ul><li>a) variable </li></ul><ul><li>i) spontaneous remission or renal failure w/in 10-15 yrs </li></ul><ul><li>b) persistent proteinuria w/ normal function </li></ul><ul><li>c) better response to corticosteroids in children vs. adults </li></ul>www.freelivedoctor.com
  175. 175. d) Progression of disease i) stage I : small granular subepithelial deposits ii) stage II : “spikes” of BM protrude between deposits of electron dense material (e.g., IgG, C3) iii) stage III : deposits of electron dense material are incorporated into GBM iv) stage iv : GBM very distorted and damaged www.freelivedoctor.com
  176. 176. www.freelivedoctor.com
  177. 177. <ul><li>Minimal change disease (Lipoid </li></ul><ul><li>nephrosis; (Epithelial cell disease)) </li></ul><ul><li>a) major cause of nephrotic syndrome in </li></ul><ul><li>b)  children < 15 yrs; peak 2-6 yrs i) also in adults with nephrotic syndrome (~ 20 %) </li></ul><ul><li>c) effacement of “foot” processes </li></ul><ul><li>d) glomeruli show only “minimal” changes </li></ul><ul><li>e) most patients are boys who usually present prior to 6 yrs of age </li></ul><ul><li>i) selective proteinuria (albumin) </li></ul><ul><li>ii) history of recent Ag exposure ?? </li></ul><ul><li>f) idiopathic (sometimes follows respiratory infection or routine immunizations) </li></ul>www.freelivedoctor.com
  178. 178. Minimal Change Disease www.freelivedoctor.com
  179. 179. www.freelivedoctor.com
  180. 180. g) T cell involvement suggested i) HL patients present w/ similar S & S ii) epithelial cell diseases have altered T ell function h) loss of lipoproteins through the glomeruli  accumulates lipids in proximal tubule cells  foamy cytoplasm. Together with lipids in the urine  LIPOID NEPHROSIS i) remission w/in 8 weeks with use of corticosteroid use (very dramatic response is one hallmark of this disease) j) relapses do not tend to progress to chronic renal failure www.freelivedoctor.com
  181. 181. <ul><li>k) development of azotemia should suggest incorrect diagnosis of minimal change disease </li></ul><ul><li>l) in absence of complications, outcome of patients with epithelial cell disease is same as general population </li></ul><ul><li>Focal segmental glomerulosclerosis </li></ul><ul><li>(epithelial cell and BM disease) </li></ul><ul><li>a) some glomeruli exhibit segmental areas of sclerosis whereas others are normal </li></ul><ul><li>b) nephrotic syndrome </li></ul><ul><li> </li></ul>www.freelivedoctor.com
  182. 182. c) occurs in the following setting: i) associated with other conditions - HIV - heroin addiction - sickle cell disease - morbid obesity ii) secondary event - IgA nephropathy iii) adaptive process to loss of kidney - renal ablation - advanced stages of other renal diseases (e.g., hypertension) iv) primary disease (e.g., idiopathic focal segmental glomerulosclerosis) www.freelivedoctor.com
  183. 183. d) most common cause of nephrotic syndrome in USA i) Hispanics and African Americans e) differs from minimal change disease i) higher incidence of hematuria, reduced GFR, and hypertension ii) poor response to corticosteroids iii) proteinuria is non selective iv) progression to chronic glomerulosclerosis v) IgM and C3 trapping on sclerotic segments www.freelivedoctor.com
  184. 184. vi) whether this is a specific disease or is an evolution of minimal change disease is unresolved !! - degeneration of visceral epithelial cells hallmark of FSGS - similar cell damage as seen in minimal change disease vii) genetic basis - NPHS1 gene  encodes nephrin - several mutations of this gene give rise to congenital nephrotic syndrome of the Finnish type (CNF) www.freelivedoctor.com
  185. 185. Focal segmental glomerulosclerosis www.freelivedoctor.com
  186. 186. <ul><li>- NPHS2 gene </li></ul><ul><li>- encodes to podocin </li></ul><ul><li>- mutations give rise to steroid resistant nephrotic syndrome in children </li></ul><ul><li>Paraproteinemic nephropathies </li></ul><ul><li>a) abnormally elevated immunoglobulin or </li></ul><ul><li> immunoglobulin fragments (i.e., paraproteins) may cause renal disease </li></ul><ul><li>i) present in blood and/or urine </li></ul><ul><li>ii) renal diseases include </li></ul><ul><li>- multiple myeloma </li></ul><ul><li>- Waldenstrom macroglobulinemia </li></ul><ul><li>- cryoglobulinemia </li></ul>www.freelivedoctor.com
  187. 187. <ul><li>Multiple myeloma </li></ul><ul><li>a) neoplasm of Ig producing plasma cells </li></ul><ul><li>b) occurs in 5 th decade </li></ul><ul><li>c) more than 50% of all patients with multiple myeloma have renal involvement </li></ul><ul><li>i) hypercalcemia </li></ul><ul><li>ii) hyperuricemia </li></ul><ul><li>iii) renal infections </li></ul><ul><li>iv) renal lesions are of three types </li></ul><ul><li>- tubular and interstitial lesions </li></ul><ul><li>- amyloidosis </li></ul><ul><li>- light chain deposition disease </li></ul>www.freelivedoctor.com
  188. 188. 2. Waldenstrom macroglobulinemia a)  serum IgM b)  blood viscosity c) renal involvement results in partial or total occlusion of glomerular capillaries 3. Cryoglobulinemia a) IgM or IgG b) defined by their capacity to precipitate at 4  C c) renal disease is often immune complex mediated d) microthrombi in glomeruli e) mesangial & endothelial cell proliferation www.freelivedoctor.com
  189. 189. <ul><li>Hereditary nephritis (Alport syndrome) </li></ul><ul><li>a) most often present as recurrent hematuria </li></ul><ul><li>b) structural defects in GBM </li></ul><ul><li>i) specific molecular defect affecting type IV collagen </li></ul><ul><li>c) usually does not present with nephrotic syndrome and proteinuria </li></ul><ul><li>d) more severe in men </li></ul><ul><li>i) die by age 40 </li></ul><ul><li>e) progressive hearing loss (high frequencies) </li></ul><ul><li>f) ocular defects most often  the lens </li></ul>www.freelivedoctor.com
  190. 190. <ul><li>Benign familial hematuria (thin GBM </li></ul><ul><li>disease) </li></ul><ul><li>a) presents as recurrent hematuria in childhood or young adults (similar to Alport syndrome) </li></ul><ul><li>b) no progression to renal failure (unlike Alport syndrome) </li></ul><ul><li>c) reduced thickness of GBM (capillary site) </li></ul><ul><li>d) one of most important causes of asymptomatic hematuria </li></ul><ul><li>e) IgA nephropathy and this disease are two most major diagnostic considerations of asymptomatic hematuria </li></ul>www.freelivedoctor.com
  191. 191. <ul><li>GLOMERULAR LESIONS ASSOCIATED WITH SYSTEMIS DISEASES </li></ul><ul><li>Diabetic glomerulosclerosis (Kimmelstiel- </li></ul><ul><li>Wilson Disease) </li></ul><ul><li>a) diabetic microangiopathy </li></ul><ul><li>i) small arteries, arterioles and capillaries) </li></ul><ul><li>- hyaline arteriosclerosis in diabetics involves both afferent and efferent arterioles </li></ul>www.freelivedoctor.com
  192. 192. ii) occur by progressive accumulation of GBM material - severity and duration of hyperglycemia !! ?? b) etiology of proteinuria not known i) non-nephrotic proteinuria ii) nephrotic c) earliest lesion is thickening of GBM d) followed by glomerular enlargement e) “diffuse glomerulosclerosis” refers to enlarged glomeruli w/expanded mesangium and diffusely thickened GBM www.freelivedoctor.com
  193. 193. f) nodular glomerulosclerosis (i.e., Kimmelstiel-Wilson Disease) – highly specific for diabetes g) one of leading causes of chronic renal failure in USA h) 2 processes play role in diabetic glomerular lesions i) metabolic defect (i.e., glycosylation end products that: -  GBM thickening -  mesangial matrix ii) hemodynamic effects: - glomerular hypertrophy (  GFR) - develop of glomerulosclerosis www.freelivedoctor.com
  194. 194. Diabetic glomerulosclerosis www.freelivedoctor.com
  195. 195. <ul><li>I) Clinical </li></ul><ul><li>i) proteinuria usually mild </li></ul><ul><li>ii) nephrotic syndrome present  renal failure w/in 6 yrs. </li></ul><ul><li>- severe proteinuria usually associated with other signs of advanced diabetes (i.e., retinopathy) </li></ul><ul><li>Amyloidosis </li></ul><ul><li>a) deposits of amyloid w/in glomeruli </li></ul><ul><li>i) mostly light chain AA or AL type </li></ul><ul><li>ii) Congo red amyloid positive deposits mainly in mesangium and capillaries </li></ul>www.freelivedoctor.com
  196. 196. Amyloid nephropathy www.freelivedoctor.com
  197. 197. <ul><li>b) clinical </li></ul><ul><li>i) nephrotic syndrome </li></ul><ul><li>ii) progressive glomerular destruction leads to death from uremia </li></ul><ul><li>Henoch-Schönlein Purpura </li></ul><ul><li>a) purpuric skin lesions on legs, arms and buttock </li></ul><ul><li>b) abdominal pain, vomiting, intestinal bleeding, arthralgias and renal abnormalities (hematuria, proteinuria, nephrotic syndrome) </li></ul><ul><li>c) not all these S & S need to be present </li></ul>www.freelivedoctor.com
  198. 198. d) disease most common in children i) 3-8 yrs e) does occur in adults where disease is more severe i) may develop rapidly progressive form of glomerulornephritis with many crescents f) onset often follows upper respiratory infection i) IgA deposits in mesangium which has led to concept that IgA nephropathy (purely a renal disease) and Henoch-Schönlein Purpura are spectra of same disease www.freelivedoctor.com
  199. 199. <ul><li>Glomerular Diseases (INFLAMMATORY) </li></ul><ul><li>(“GLOMERULONEPHRITIS”) </li></ul><ul><li>Inflammatory lesions of glomerulus </li></ul><ul><li>characterized by hypercellularity which </li></ul><ul><li>may be diffuse or focal + proliferation </li></ul><ul><li>a) Diffuse types of glomerulornephritis </li></ul><ul><li>i) post infectious </li></ul><ul><li>ii) membranoproliferative </li></ul><ul><li>iii) some lupus forms </li></ul><ul><li>b) Focal types of glomerulornephritis </li></ul><ul><li>i) IgA </li></ul><ul><li>ii) other lupus forms </li></ul>www.freelivedoctor.com
  200. 200. c) glomerular injury may be either global (entire glomerulus) or segmental d) glomerulornephritis clinically characterized by the NEPHRITIC SYNDROME i) may present with only portions of these S & S (i.e., hematuria) ii) on occasion, proteinuria may predominate e) different forms of GN are differentiated via microscopy www.freelivedoctor.com
  201. 201. f) neutrophils contribute to  cellularity, particularly in children i) many neutrophils in glomeruli referred to as “exudative” g) proliferation of podocytes and Bowman’s capsule (visceral and parietal epithelium, respectively) i) leads to formation of “crescents” - highly cellular lesions - extend from Bowman’s capsule into glomerulus having shape of crescents. These are severe lesions (associated with necrosis, early and late fibrosis) www.freelivedoctor.com
  202. 202. <ul><li>Pathogenesis of inflammatory GN </li></ul><ul><li>Immunologic injury </li></ul><ul><li>a) trapping of circulating immune complexes </li></ul><ul><li>b) in situ immune complex formation </li></ul><ul><li>c) activation of alternative complement </li></ul><ul><li>d) cell mediated processes </li></ul><ul><li>Circulating immune complex nephritis </li></ul><ul><li>a) glomerular trapping of circulating Ag-Ab v complexes. </li></ul><ul><li>i) glomerulus as “innocent bystander” </li></ul><ul><li>- penetrate GBM than are  </li></ul><ul><li>- trapped in GBM </li></ul>www.freelivedoctor.com
  203. 203. b) confirmed by EM i) presence of subepithelial “humps” ii) peripheral granular staining directed - IgG - C3 c) alternatively, circulating immune complex do not penetrate GBM but localize to i) mesangium or subendothelium d) trapping is affected by: i) size and charge of aggregates ii) glomerular hemodynamics iii) presence of vasoactive substances www.freelivedoctor.com
  204. 204. e) Ag may be exogenous or endogenous i) exogenous - bacterial Ag induced by 1. Strep infections 2. bacterial endocarditis 3. viruses (HBV) ii) endogenous - DNA in pathogenesis of lupus 2. In Situ immune complex formation a) Goodpasture Syndrome b) Ag (endogenous) already embedded in GBM i) Ab binds !! ii) linear localization of IgG along GBM www.freelivedoctor.com
  205. 205. c) Ag-Ab interaction activates complement ! i) rapidly progressive GN occurs 3. Alternative complement activation a) focal glomerulornephritis i) caused by IgA b) form of membranoproliferative GN 4. Cell-mediated Immunity a) no direct evidence for any specific GN caused by cell mediated processes i) indirect evidence for a delayed (type iv) cell type GN - lymphocytes from some patients with GN react in vitro with a glomerular Ag www.freelivedoctor.com
  206. 206. <ul><li>once immune complexes localized w/in GBM </li></ul><ul><li>other secondary affects cause immune </li></ul><ul><li>mediated injury  mediators: </li></ul><ul><li>a) complement (C5b-C9; cytotoxic) </li></ul><ul><li>b) neutrophils (chemotaxis via C5a) </li></ul><ul><li>c) monocytes & macrophages </li></ul><ul><li>d) coagulation system </li></ul><ul><li>NEPHRITIC SYNDROME </li></ul><ul><li>hematuria </li></ul><ul><li>oliguria </li></ul><ul><li> BUN and creatinine </li></ul><ul><li>hypertension </li></ul><ul><li>proteinuria (< 3.5 g/day); ± edema </li></ul>www.freelivedoctor.com
  207. 207. www.freelivedoctor.com
  208. 208. <ul><li>Glomerulornephritis - - INFLAMMATORY </li></ul><ul><li>Acute GN (post infectious GN) </li></ul><ul><li>a) sudden onset of nephritic syndrome </li></ul><ul><li>b) diffuse hypercellularity of glomeruli </li></ul><ul><li>c) most often associated with </li></ul><ul><li>i) group A β -hemolytic streptococci </li></ul><ul><li>- S. pyogenes </li></ul><ul><li>ii) others less frequently </li></ul><ul><li>- staph </li></ul><ul><li>- spirochetes </li></ul><ul><li>- viruses </li></ul><ul><li>d) most often affect children </li></ul><ul><li>i) one of most common renal diseases </li></ul>www.freelivedoctor.com
  209. 209. e) latent period of ~ 10-14 days f) diffuse enlargement and hypercellularity of glomeruli, hypercellularity due to: i) proliferation of endothelial and mesangial cells and infiltration of neutrophils and monocytes g) characteristics: i) subepithelial “humps” of GBM ii) granular IgG and C3 along GBM in association with “humps” h) Clinical: i) most resolve but in rare occasions can progress to develop many crescents and renal failure www.freelivedoctor.com
  210. 210. Acute GN (post infectious GN) www.freelivedoctor.com
  211. 211. <ul><li>ii) primary infection in pharynx or skin </li></ul><ul><li>iii) nephritic syndrome (abrupt) </li></ul><ul><li>- hematuria </li></ul><ul><li>- oliguria </li></ul><ul><li>- facial edema </li></ul><ul><li>- hypertension </li></ul><ul><li>iv)  serum C3 </li></ul><ul><li>Membranoproliferative GN </li></ul><ul><li>a) characterized by GBM thickening (i.e., “membrano”) + mesangial cell proliferation (“proliferative ”) </li></ul>www.freelivedoctor.com
  212. 212. b) two major groups: Types I and II (+ III) i) Type I: majority of cases are idiopathic. Associations with - HBV - HCV - bacterial endocarditis - strep infections - granular deposition of Ig (IgG, IgM) and complement (C3) and C1q and C4 ii) type II (and III) - circulating C3 Ab (C3 nephritic factor)   C3 (hypocomplementemia) www.freelivedoctor.com
  213. 213. - characteristic “ribbon-like” zone of  cellularity on thickened GBM (“dense deposit disease”) c) Clinical: i) occurs primarily in older children and young adults ii) nephritic or nephrotic syndrome iii) low levels of C3 iv) do not have postinfectious GN v) no systemic inflammatory condition vi) most progress to end-stage renal failure, regardless of treatment !! www.freelivedoctor.com
  214. 214. Membranoproliferative GN Type I www.freelivedoctor.com
  215. 215. <ul><li>SLE (immune complex disease); “Lupus </li></ul><ul><li>Nephritis” </li></ul><ul><li>a) chronic autoimmune disorder </li></ul><ul><li>b) affects 1  young women </li></ul><ul><li>c) > 70% will develop renal disease </li></ul><ul><li>d) circulating anti DNA Ab and  C3, etc. </li></ul><ul><li>i) T cell function is decreased </li></ul><ul><li>ii) trapping of immune complexes cause of the renal damage ( in situ ) </li></ul><ul><li>e) nephritic or nephrotic syndrome </li></ul><ul><li>f) dysfunction of renal tubules (usually accompanies GN) </li></ul><ul><li>g) cellular proliferation is mesangial, subepithelial and subendothelial cells </li></ul>www.freelivedoctor.com
  216. 216. i) involves the glomeruli w/more severe inflammation h) hematoxylin bodies  only light microscopic feature of tissue damage i) episodic inflammation – usually present with old lesions j) IgG most common. IgA and IgM also present. Complement present i) IgG, IgA, IgM, C3, C4 and C1q present in same glomerulus “FULL HOUSE” www.freelivedoctor.com
  217. 217. k) 5 classes based on WHO classification i) Class I – histologically normal ii) Class II – pure mesangial lesion iii) Class III – focal and segmental GN iv) Class IV – diffuse proliferative GN v) Class V – diffuse membranous - Class II and V have more benign course relative to Class III and IV l) renal disease  major consequence of SLE i) renal failure  cause of death in ~ 33 % of patients with SLE www.freelivedoctor.com
  218. 218. <ul><li>Focal GN </li></ul><ul><li>a) only some of the glomeruli are involved </li></ul><ul><li>i) or to segments of the glomerulus </li></ul><ul><li>b) different from focal & segmental glomerulosclerosis which is a noninflammatory disease </li></ul><ul><li>i) glomeruli essentially normocellular </li></ul><ul><li>c) many conditions produce this defect </li></ul><ul><li>i) primary renal disease or systemic diseases such as IgA nephropathy and Henoch-Schönlein GN (see table) </li></ul>www.freelivedoctor.com
  219. 219. d) IgA nephropathy (Berger Disease) i) association with chronic liver disease - impaired capacity to remove circulating immune complexes ii) IgA and fibronectin found in > 70 % of IgA nephropathy patients. iii) Ag involve bacterial, viral and dietary - infectious agents is suggested from data showing hematuria following upper respiratory or GI infection !! - dietary agents  milk proteins I in mesangium; gluten-sensitivity www.freelivedoctor.com
  220. 220. iv) C3 and properdin (via activation of alternate pathway) usually present together with IgA in mesangium - C1q and C4 (classic pathway activation) are typically absent v) IgA nephropathy is a mesangial proliferative lesion (granular deposits) vi) clinical - common in young men (15-30) - presents with hematuria - nephrotic type proteinuria is uncommon (may indicate more severe glomerular damage) www.freelivedoctor.com
  221. 221. - ~ 20 % of IgA nephropathy patients progress to end-stage renal failure !! - most common type of 1  GN in several parts of the world (France, Italy, Japan, Singapore and Austria) -- ~ 20 %. In USA is responsible for ~ 3-10 % of 1  GN www.freelivedoctor.com
  222. 222. IgA nephropathy (Berger Disease) www.freelivedoctor.com
  223. 223. <ul><li>e) Henoch-Schönlein (HS) Purpura </li></ul><ul><li>i) close relationship with IgA nephropathy </li></ul><ul><li>- differentiate: IgA purely renal; HS is a systemic disease, etc. </li></ul><ul><li>Crescentic GN </li></ul><ul><li>a) ominous morphological pattern </li></ul><ul><li>i) majority of glomeruli are surrounded </li></ul><ul><li> by accumulation of cells in Bowman’s capsule (parietal epithelial cells) </li></ul><ul><li>ii) indicative of fulminant glomerular damage and always leaves scarring </li></ul>www.freelivedoctor.com
  224. 224. iii) does not denote a specific etiologic form of GN b) most patients with substantial (~ 80%) crescents progress to renal failure c) Fibrin in Bowman’s capsule is important for the formation of glomerular crescents i) Tx with anticoagulants d) associated with areas of segmental necrosis within glomeruli e) Types: i) Type I – anti-GBM antibody disease (GOODPASTURE SYNDROME) or idiopathic www.freelivedoctor.com
  225. 225. - plasmapheresis to remove circulating Ab is helpful in this type of RPGN (i.e., crescentic) - etiology unknown ii) Type II – immune-complex mediated disease - can be complication of any of the immune complex nephritides  SLE, IgA nephropathy,  HS Purpura  all these show granular pattern (characteristic of immune complex) - not helped with plasmapheresis www.freelivedoctor.com
  226. 226. iii) Type III – pauci-immune type - lack of anti-GBM Ab or immune complexes - patients do have ANCA (~90%)  either c or p patterns } in some cases, is a component of vasculitides (i.e., Wegener Granulomatosis) f) clinical: i) hematuria with red cell cast in urine ii) transplant or chronic dialysis in most patients www.freelivedoctor.com
  227. 227. Crescentic GN www.freelivedoctor.com
  228. 228. <ul><li>TUBULOINTERSTITIAL DISEASE </li></ul><ul><li>Most tubular diseases involve the interstitium </li></ul><ul><li>2 distinct types of diseases </li></ul><ul><li>a) ischemic or toxic tubular injury  </li></ul><ul><li>i) ATN </li></ul><ul><li>ii) acute renal failure </li></ul><ul><li>b) inflammatory diseases </li></ul><ul><li>i) “tubulointerstitial nephritis” </li></ul><ul><li>ATN (Clinical entity) </li></ul><ul><li>Destruction of tubular epithelial cells </li></ul><ul><li>Acute suppression of renal function </li></ul>www.freelivedoctor.com
  229. 229. <ul><li>Most common cause of acute renal failure: </li></ul><ul><li>a) oliguria (< 400 ml/day) </li></ul><ul><li>b) severe glomerular disease (RPGN) </li></ul><ul><li>c) acute thrombotic angioplasties </li></ul><ul><li>d) diffuse renal vascular disease (Polyarteritis nodosa) </li></ul><ul><li>e) diffuse cortical necrosis </li></ul><ul><li>f) interstitial nephritis (acute drug- induced) </li></ul><ul><li>g) acute papillary necrosis </li></ul>www.freelivedoctor.com
  230. 230. <ul><li>Is reversible and arise from: </li></ul><ul><li>a) severe trauma </li></ul><ul><li>b) septicemia (shock and hypotension) </li></ul><ul><li>c) ATN associated with shock – “ischemic” - d) mismatched blood transfusion and other hemodynamic problems as well as myoglobinuria  all reversible ischemic </li></ul><ul><li> ATN </li></ul><ul><li>e) nephrotoxic ATN – variety of poisons </li></ul><ul><li>i) heavy metals (Hg) </li></ul><ul><li>ii) CCl4 </li></ul><ul><li>iii) etc. </li></ul>www.freelivedoctor.com
  231. 231. <ul><li>Occurs frequently </li></ul><ul><li>a) since it is reversible, proper management means difference between recovery and death </li></ul><ul><li>2 major problems are: </li></ul><ul><li>a) tubular injuries </li></ul><ul><li>b) blood flow disturbances </li></ul><ul><li>Major disturbances: </li></ul><ul><li>a) Change charge in tubules (mainly -) </li></ul><ul><li>i) Na+ - K+ - ATPase cause </li></ul><ul><li> less Na+ reabsorption and traps Na+, within tubule with more distal tube delivery of Na+ which causes </li></ul><ul><li> vasoconstriction (feedback) </li></ul>www.freelivedoctor.com
  232. 232. <ul><li>Treatment protocol </li></ul><ul><li>1) - initiating phase </li></ul><ul><li>2) - maintenance phase </li></ul><ul><li>3) - recovery phase </li></ul><ul><li>Initiating phase </li></ul><ul><li>Last about 36 hours. Incited by: </li></ul><ul><li>a) medical, surgical, obstetric event </li></ul><ul><li>i) slight oliguria (transient decrease in blood flow) </li></ul><ul><li>ii) rise in BUN </li></ul>www.freelivedoctor.com
  233. 233. <ul><li>Maintenance phase </li></ul><ul><li>Anywhere from 2-6 days </li></ul><ul><li>a) sharp decline in urine output (50-400 ml/day) </li></ul><ul><li> i) may last few days to 3 weeks </li></ul><ul><li>b) fluid overload, uremia </li></ul><ul><li>c) may die from poor management </li></ul><ul><li>Recovery phase </li></ul><ul><li>Steady increase in urine output (up to 3L/day) </li></ul><ul><li>Electrolyte imbalances may continue </li></ul><ul><li>Increased vulnerability to infection </li></ul><ul><li>Because of these, about 25% patients die in </li></ul><ul><li>this phase </li></ul>www.freelivedoctor.com
  234. 234. <ul><li>Tubulointerstitial Nephritis (TIN) </li></ul><ul><li>Inflammatory disease of Interstitium/tubules </li></ul><ul><li>Glomerulus no

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